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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 6Recurring Chromosome Rearrangements in Human Cancer

, MD, , MD, and , MD.

Acquired clonal chromosomal abnormalities are found in the malignant cells of most patients with leukemia, lymphoma, and solid tumors. Many genes involved in consistent chromosome rearrangements, notably translocations, have already been identified, and the identity of most genes affected by these aberrations likely will be determined within the next decade. The Human Genome Project, with its ambitious goal of identifying all human genes, has increased the pace at which new cancer-related genes are identified. Moreover, for a number of rearrangements, some of the changes in gene structure and function have been defined; therefore, some general principles that may be applicable to all chromosome rearrangements in human malignant disease are beginning to emerge. This review presents the most current data on primary chromosome rearrangements in hematologic malignancies and solid tumors.

Much of the detailed information regarding the relevant chromosome rearrangements is contained in a number of recent reviews, and only a general summary is presented here.1–5 Mitelman has published five editions of his Catalog of Chromosome Aberrations in Cancer, which describes the cytogenetic aberrations in more than 46,000 neoplasms.2 This catalogue is now available as a CD ROM (1998). In addition, a map of recurrent chromosomal rearrangements was published recently,6 and the National Cancer Institute maintains a Website with an updated map (Cancer Chromosome Aberration Project: Although solid tumors such as lung, breast, and prostate cancer account for the greatest proportion of malignant disease, they represent only a small fraction of the karyotypic data. From the beginning of cytogenetic analysis of human malignant disease, it has been clear that virtually all solid tumors, including the non-Hodgkin’s lymphomas, have an abnormal karyotype and that some of these abnormalities are limited to a given tumor type.1,7,8 In the 1960s and 1970s, only approximately 50% of leukemias had identifiable karyotypic abnormalities, but now over 80% have an abnormal karyotype. This increase has occurred because of improved culture techniques and processing methods. Certain malignant diseases, such as Hodgkin’s disease or multiple myeloma, continue to show a high frequency of normal karyotypes, probably because of their low mitotic index; however, the use of fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), and spectral karyotyping (SKY) (Fig. 6.1A and Fig. 6.1B) or multicolor FISH (M-FISH) is adding a new precision in chromosome identification that will have a major impact. “Painting” probes identify chromosomes that are involved in rearrangements or in marker chromosomes;9 centromere-specific probes allow enumeration of the number of chromosomes in interphase nuclei, and; region-specific probes can detect deletions and translocations.9

Figure 6.1A. Standard G banded karyotype from a 44-year-old male with acute myelomonocytic leukemia (M4).

Figure 6.1A

Standard G banded karyotype from a 44-year-old male with acute myelomonocytic leukemia (M4). The original karyotype was 41,add(X)(q22),-Y,-5,del(7)(q11q36),inv(11)(p15q23),dic(12;?)(p12;?),-13,del(15)(q15q22),-16,add(17)(p13),-19,-20,-21,I(21)(q10),+mar1,+mar2. (more...)

Figure 6.1B. Analysis of a single cell using spectral karyotyping (SKY).

Figure 6.1B

Analysis of a single cell using spectral karyotyping (SKY). The upper left figure is the metaphase cell stained with DAPI, the upper middle figure is the spectral image, the upper right is the classified image, and the lower panel is the spectral karyotype. (more...)

Different chromosome changes have been observed in neoplastic cells, and these often occur in combination, which leads to great difficulty in identifying the critical abnormalities in a particular cancer precisely. A number of international meetings over the last 25 years led to the establishment of a universally accepted system for chromosome nomenclature, which is used here (the International System for Human Cytogenetic Nomenclature [ISCN, 1995]).10

The simplest change is either a gain or a loss of a whole chromosome. Common structural alterations are translocations, which involve the exchange of material between two or more chromosomes, and deletions, which involve the loss of DNA from a chromosome and, thus, from the affected cell (Fig. 6.2). Chromosome inversions have also been observed; in this rearrangement, a single chromosome is broken in two places and the central portion inverted and rejoined to the ends of the chromosome. Each chromosome band is numbered.10 The chromosome number of the clone (modal number) is followed by the sex chromosomes, and gains and losses of whole chromosomes are identified by a “+” or a “–” before the chromosome number, respectively; “p” and “q” represent the short and the long arms, respectively. Deletions are indicated by the abbreviation “del.” Translocations are indicated by “t,” with the chromosomes involved noted in the first set of brackets and the breakpoints in the second set (Table 6.1). For structural abnormalities, clonal abnormalities are defined as those that are present in at least two cells. Loss of a chromosome must occur in three cells to be considered a clonal abnormality. Banding of chromosomes is essential to cytogenetic investigations because it allows the identification of individual chromosomes. A band is defined as a chromosome area that is distinguished from adjacent segments by appearing darker or lighter through one or more banding techniques. Various banding methods are currently used, including quinacrine-mustard (Q bands) and trypsin-Giemsa banding (G bands).

Figure 6.2. Schematic diagram illustrating a normal chromosome and three chromosomal abnormalities observed in human neoplasms.

Figure 6.2

Schematic diagram illustrating a normal chromosome and three chromosomal abnormalities observed in human neoplasms. A. Diagram of the banding pattern of a normal chromosome 9. The chromosome arms (p, short arm; q, long arm), regions, and band numbers (more...)

Table 6.1A. Glossary of Cytogenetic Terminology.

Table 6.1A

Glossary of Cytogenetic Terminology.

Table 6.1B. Karyotype Symbols.

Table 6.1B

Karyotype Symbols.

In addition to FISH, CGH and SKY have proven to be particularly powerful in the identification of genetic alterations associated with hematologic malignancies and solid tumors.3,9,11 FISH is a technique in which the appropriate DNA probes are labeled with various fluorochromes (e.g., rhodamine) that are detected by fluorescence microscopy. A large number of chromosome-specific centromere probes are now available that unequivocally mark a pair of chromosomes. Using these probes, gains or losses of chromosomes can be detected not only in metaphase chromosomes but also in interphase cells. Large-size DNA probes that contain specific genes or anonymous DNA sequences (e.g., yeast artificial chromosomes, P1, BACs) can be used to screen for recurring translocations and to identify those probes that are split by the translocation breakpoints. Currently, this technique is widely used by many groups in their search for genes involved in different translocations.9 CGH is a new in situ hybridization-based procedure to detect and map relative gene copy aberrations (both gains and losses) in the tumor genome onto normal metaphase chromosomes.11 This technique is powerful because it does not require advanced knowledge of the existence or genetic location of altered copy-number regions or cell culture, thereby eliminating the possibility of subpopulation selection during the culture. Changes in relative gene copy number detected using CGH may be associated with oncogene amplification or loss of tumor-suppressor gene function.

The newest technique is SKY or M-FISH. DNA from each human chromosome pair is labeled with a single or multiple fluors and is applied in a cocktail to the sample containing malignant cells. Using various systems to capture and analyze the image, one can detect all of the chromosome abnormalities in a single experiment (see Fig. 6.1).3,12,13 SKY analysis identifies the chromosomes involved but not the specific region of the chromosome.

To be relevant to the malignant disease, chromosomes for analysis must be obtained from the tumor cells. Thus, for leukemia, bone marrow cells or peripheral blood cells processed directly or after 24- to 72-hour culture are used; lymph nodes or solid tumors are minced to yield a single cell suspension that can be harvested immediately or cultured for a short period of time. The cells are exposed to a hypotonic solution, fixed, and stained according to a variety of protocols.14,15 Combined with a brief exposure to mitotic inhibitors such as colchicine or use of DNA-binding agents to elongate chromosomes, use of amethopterin or fluorodeoxyuridine to synchronize cells has resulted in longer chromosomes that have an increased number of bands as well as improved morphology. The addition of PHA-stimulated conditioned medium or recombinant colony-stimulating factors to the culture medium also has contributed to the increased rate of successful cytogenetic analysis of different tumors. Cytogenetic analysis requires specimens that contain viable dividing cells; therefore, specimens should be transported without delay to the cytogenetics laboratory in a suitable culture medium at room temperature.

Myeloproliferative Disorders

Chronic Myeloid Leukemia

The first consistent chromosome abnormality in any malignant disease was the Philadelphia or Ph1 chromosome (now called the Ph chromosome) identified in chronic myeloid leukemia (CML).16 This abnormality was thought to be a deletion of chromosome 22 (22q-) but was later shown to be a translocation involving chromosome 9 and 22 [t (9;22)(q34;q11)] (see Fig. 6.2).17

The Philadelphia chromosome occurs in a pluripotential stem cell that gives rise to cells of both lymphoid and myeloid lineage. The reciprocal nature of the translocation was established in 1982, when the Abelson proto-oncogene, ABL, which is normally on chromosome 9, was identified on the Ph chromosome.18 This ultimately led to cloning of the breakpoint involved in the t(9;22).19 The site on the Ph chromosome was called bcr, for breakpoint cluster region, which in the majority of translocations cluster in a small, 5.8-kb region.19 In contrast, the breaks on chromosome 9 occur over an incredible distance of more than 200 kb.20 The genetic consequence of the t(9;22) is to move the ABL gene, a nonreceptor tyrosine kinase on chromosome 9, next to the BCR gene on chromosome 22. This translocation creates two new genes, BCR-ABL on the 22q- or Phi chromosome, and the reciprocal ABL-BCR on the derivative 9q+. Whether the latter fusion gene, although transcriptionally active, plays a role in the disease is controversial. Depending on the breakpoint in the BCR gene, three main types of BCR-ABL gene can be formed.21 The predominant hybrid gene in classic CML is derived from a disruption in the major breakpoint cluster region (M-bcr). Transcription from this gene yields chimeric mRNA molecules. The final product of this genetic rearrangement is a 210kDa cytoplasmic fusion protein or p210BCR-ABL, the transforming protein responsible for most, if not all, phenotypic abnormalities of chronic phase CML. The leukemogenic nature of the BCR-ABL protein results from the fact that its ABL-derived tyrosine kinase function is constitutively activated, presumably through dimerization of the BCR portion of the fusion protein.22 Knowledge of the molecular consequence of the consistent chromosome abnormality seen in CML, together with the availability of sophisticated biochemical and biophysical technology, has allowed the development of molecularly targeted therapies for CML. Several tyrosine kinase inhibitors have been evaluated in CML and one such compound, STI571, administered orally has resulted in dramatic responses in some patients with CML.23

The appearance of new abnormalities in the karyotype of a patient with CML often signals a change in the pace of the disease, usually to a more aggressive disorder. When patients with CML enter the terminal acute phase, approximately 10 to 20% appear to retain the chromosome 46, Ph-positive cell line unchanged; however, most patients show additional chromosomal abnormalities, which result in cells with modal chromosome numbers of 47 to 50. During the acute phase of CML, different chromosomal abnormalities occur either singly or in combination, in a distinctly nonrandom pattern. In patients with only a single new chromosome change, this most commonly involves a second Ph chromosome, an isochromosome for the long arm of chromosome 17 [i(17q)], or a + 8, in descending order of frequency. Chromosome loss is rare, but when it happens, a - 7 is seen, which occurs in 3% of patients.

Marrow cells from some patients who appear to have CML on both clinical and morphologic grounds lack a Ph chromosome. Most of these patients had a normal karyotype, and, somewhat surprisingly, their survival was substantially shorter than those whose cells were Ph+.24 Reviews of two series of such patients showed they did not have CML but rather some type of myelodysplasia, most commonly chronic myelomonocytic leukemia or refractory anemia with excess blasts, leading to their shorter survival.25,26 The situation has become more complex, however, because molecular analysis has shown that some patients with clinically typical CML who lack a Ph chromosome cytogenetically have evidence for the insertion of ABL sequences into the BCR gene.25,27 Thus, it is clear that the sine qua non of CML is the juxtaposition of BCR and ABL with the formation of a fusion transcript BCR-ABL.27,28,29 Several research groups are working to unravel the genetic consequences of the Ph chromosome.22,29

Acute Myeloid Leukemia De Novo

At present, at least 80% of patients with acute myeloid leukemia (AML) have an abnormal karyotype. Specific rearrangements are closely associated with particular subtypes of AML as defined by the French-American-British Cooperative Group30 (FAB classification) (Fig. 6.3). This association has been incorporated into the recent WHO classification (XX). The chromosomal abnormalities associated with each subtype and their frequency are summarized in Table 6.2.

Figure 6.3. Partial karyotypes from trypsin-Giemsa-banded metaphase cells depicting nonrandom chromosomal rearrangements observed in myeloid malignant diseases.

Figure 6.3

Partial karyotypes from trypsin-Giemsa-banded metaphase cells depicting nonrandom chromosomal rearrangements observed in myeloid malignant diseases. (a) t(9;22)(q34;q11), CML; (b) t(8;21)(q22;q22), AML-M2; (c) inv(16)(p13q22), AMMoL-M4Eo; (d) t(15;17)(q22;q11-12), (more...)

Table 6.2. Nonrandom Chromosome Abnormalities in Malignant Myeloid Diseases.

Table 6.2

Nonrandom Chromosome Abnormalities in Malignant Myeloid Diseases.

Over the past decade, the explosion of molecular biology research and improvement in molecular techniques has led to the identification of and study of genes involved in recurring chromosomal translocations in cancer. Although a large number of translocations have been cloned, many of the genes identified have been found to be common to certain pathways that are now postulated as being important in malignant transformation.

Chromosomal rearrangements involving core binding factor (CBF)

These include the t(8;21)(q22;q22), t(3;21)(q26;q22), inv(16)(p13q22) and t(16;16)(p13;q22). The t(12;21)(p13;q22) also involves CBF, but the phenotype of the leukemia that results is acute lymphoblastic leukemia (ALL), and this will therefore be discussed in the section on lymphoid malignancies. AML1 has been identified in 12 different translocations, of which five have been cloned.

The translocation between chromosomes 8 and 21 [t(8;21) (q22;q22)] was first identified in 1972 and was the first translocation to be discovered (see Fig. 6.3).31 The translocation is seen primarily in patients with AML-M2 (acute myeloblastic leukemia with maturation). The t(8;21) is one of the most frequent chromosomal abnormalities in AML and is found in up to 15% of patients. The majority of patients exhibit an FAB M2 morphology and have a favorable response to chemotherapy.32 In fact, the t(8;21) is a distinct category in AML-M2 (XX). The translocation results in fusion of the AML1 gene (also known as CBFA2) on chromosome 21 to the ETO gene on chromosome 8. The fusion of these genes on the der(8) chromosome produces a chimeric AML1/ETO gene. The AML1/ETO fusion transcript is consistently detected in patients with the t(8;21) by RT-PCR even as long as 10 years after attaining a complete cytogenetic and morphologic remission.33,34

The AML1 gene encodes a sequence-specific DNA-binding protein that demonstrates 69% identity over a central 128 residues domain with the Drosophila pair-rule gene runt. DNA binding is mediated through the runt-homology domain. AML1 binds DNA as a heterodimeric complex. This complex, also known as CBF, consists of the AML1 DNA binding subunit and a second subunit, CBFß, which increases the DNA binding affinity of AML1. CBF has been shown to be important in the transcriptional activation of genes crucial for hematopoiesis. These include but are not limited to MCSF, GMCSF, and myeloperoxidase genes, IL-3, and the T-cell receptor enhancer. Murine models in which the AML1 gene has been targeted by homologous recombination have been constructed. Mice heterozygous for the mutation were phenotypically normal. Homozygous mutation of the gene (i.e., is deletion of both copies of the murine AML1 gene) is an embryonic lethal mutation. The embryos lack fetal liver hematopoiesis and die of central nervous system hemorrhage at day 12.5. Furthermore, embryonic stem (ES) cells with deletion of the gene do not contribute to hematopoiesis in chimeric animals, underscoring the importance of AML1 target genes in normal hematopoiesis.35

The mechanism of malignant transformation by AML1/ETO has not been fully elucidated, but the fusion product has dominant inhibitory activity of transcriptional activation by AML1.36 Recent studies have shown that the AML1/ETO fusion is associated with a histone deacetylase complex that inhibits normal AML1 function.37 It therefore appears that the AML1-ETO fusion protein acts as a dominant negative inhibitor of wild-type AML1 gene function. This has been further demonstrated in AML1/ETO “knock-in” mice experiments, in which mice heterozygous for the AML1/ETO allele and wild-type AML1 gene are generated by homologous recombination. These animals have the same phenotype as mice with deletion of the AML1 gene (i.e., embryonic lethality), suggesting that the fusion gene blocks normal transcription of wild-type AML1.

The t(3;21)(q26;q22) has been detected in patients with MDS and CML blast crisis. The genes cloned at this translocation breakpoint have been AML1, on band 21q22 fused to EVI1, EAP, or MDS1 on band 3q26. The fusion transcripts retain the AML1 DNA-binding domain and can therefore dimerize with CBFß, possibly inhibiting transcription of wild-type AML1. In addition, there is evidence that the EVI1 portion of the fusion may be equally important for malignant transformation.38,39 Establishing that the CBF subunit fusion proteins directly induce leukemia in vivo has been difficult because of the essential nature of the genes involved. Previous knock-in mice experiments, mentioned above, have resulted in embryonic lethality. To circumvent this problem, a recent study has employed a bone marrow retroviral transduction/transplantation approach to study the effects of the t(3;21) AML1/MDS1/EVI1 (AME) fusion gene on leukemogenesis. Expression of the AME fusion protein in mouse bone marrow cells induced a disease similar to human acute myelomonocytic leukemia.38

Another clinical-cytogenetic association that has been identified involves myelomonocytic leukemia with eosinophils that have unique morphologic changes (M4EO). Chromosomal abnormalities associated are inv(16)(p13q22) or t(16;16)(p13;q22). The strong correlation between abnormal eosinophils and structural rearrangements of chromosome 16 was confirmed at the Fourth International Workshop on Chromosomes in Leukemia (IWCL).40 This chromosomal abnormality, which is present in approximately 25% of patients with AMMoL M4, is associated with a favorable prognosis.32,41

The gene involved at 16q22 is core binding factor-beta (CBFB) and that at 16p13 is the smooth muscle myosin heavy-chain gene (MYH11).42 Both genes are transcribed from centromere to telomere. In both the inversion and translocation, the critical genetic event is the fusion of the 5' part of CBFB with the 3' part of the MYH11 gene.

The fusion transcript can be detected by FISH and RT-PCR.43 The fusion protein retains its ability to interact with AML1(CBFA) and is thought to act as a dominant negative inhibitor of wild-type AML1 function. CBFß-MYH11 knock-in mice have been developed that have a phenotype identical to that of AML1/ETO knock-in mice and to mice with homozygous mutation of AML1, thus supporting this hypothesis.44

Translocations involving RARA

A structural rearrangement involving chromosomes 15 and 17 in acute promyelocytic leukemia (APL) was first recognized in 1977 [t(15;17)(q22;q12-21)] (see Fig. 6.3).45 This rearrangement is unique to APL, or to the hypogranular variant. The translocation has been cloned. The gene at the breakpoint on chromosome 17 is the α chain of the retinoic acid receptor (RARA), whereas that on chromosome 15 is called PML.46,47 The critical junction is located on the der(15) chromosome and consists of the 5' portion of PML fused to virtually all of the RARA gene. The fusion transcript can be detected with RT-PCR.47 Other less common variant translocations involving RARA include the t(11;17)(q23;q12-21), t(5;17)(q35;q12-21), and t(11;17)(q13;q12-21).48,49 These translocations fuse the RARA gene on 17q12 to the PLZF and NPM and NUMA genes, respectively.

The t(15;17) that results in PML-RARA fusion gene is the most common and best studied to date.46 Patients have classic APL with characteristic AML-M3 morphology, which includes a dramatic accumulation of promyelocytes in the bone marrow and presence of Auer rods within the cytoplasm of the promyelocytic blasts. This is accompanied clinically by hemorrhagic diathesis. These patients have a dramatic response to all-trans retinoic acid (ATRA) therapy that tends to be short-lived unless it is followed by conventional chemotherapy. The RARA gene encodes the retinoic acid receptor alpha protein that belongs to the nuclear steroid/thyroid hormone receptor superfamily. It is a transcriptionally active protein that contains two zinc finger DNA-binding domains and a ligand-binding domain that interacts with retinoic acid receptor X (RXR). The PML-RARA fusion gene is thought to interfere with wild-type RARA function in a dominant manner.

Murine models have been created that underscore the importance of the fusion gene in leukemogenesis. When placed under the control of the human myeloid/promyelocytic specific cathepsin-G (hCG) gene or the human migration inhibitory factor related protein (hMRP8) expression cassette, the fusion gene results in development of acute leukemia in transgenic mice. However, only approximately 10 to 20% of the mice developed leukemia over a variable latency period (as long as 1 year), although all of the mice developed a preceeding myeloproliferative disorder.50,51 This suggests that PML-RARA is necessary but not sufficient to cause full-blown APL. Additional mutations are needed for the expression of the fully malignant phenotype.

As mentioned above, the APL blasts with a t(15;17) are exquisitely sensitive to the differentiating action of ATRA. ATRA is thought to override the dominant negative inhibition of wild-type RARA by PML-RARA (similar to the AML1-ETO fusion) PML-RARA fusion protein interacts with a complex of molecules known as nuclear co-repressors and histone deacetylase. This complex binds to the fusion protein and blocks transcription of target genes. ATRA interacts with RARA portion of the complex to cause release of the co-repressor complex, allowing transcription of these target genes to proceed and probably resulting in differentiation of leukemic blasts. However, APL associated with the PLZF-RARA fusion shows a distinctly worse prognosis with no response to ATRA and a poor response to chemotherapy. This may be explained by the fact that PLZF itself interacts with the nuclear co-repressor histone deacetylase complex and is able independently to block transcription of target genes and is therefore not ATRA sensitive.52

Translocations involving 11q23

The human chromosome band 11q23 is associated with an astonishing number of recurrent chromosomal abnormalities including translocations, insertions, and deletions. It is involved in over 20% of acute leukemias. The cloning of the 11q23 breakpoint region revealed the MLL (Myeloid-Lymphoid Leukemia or Mixed-Lineage Leukemia) gene, named for its involvement in myeloid (usually monoblastic) and lymphoblastic leukemia, and less commonly lymphoma.53 It is also involved in myelodysplastic syndrome, biphenotypic leukemia, and therapy-induced AML (particularly following treatment with topoisomerase II inhibitors.)54 This gene (also known as ALL1, HRX, and HTRX-1) spans 100 kb and encodes a large and complex protein with several regions of homology to Drosophila trithorax(trx) protein.55–57 Leukemias involving the MLL gene have a poor prognosis, although recent data suggest that the t(9;11) may respond better than other MLL translocations.32,58

The MLL protein comprises 3968 amino acids and contains several domains.54,57,59 These include the AT-hook DNA-binding domain near the amino terminus, which binds AT-rich cruciform DNA recognizing structure, rather than a specific sequence.59 This region is similar to the AT-hook of high-mobility group (HMG)I(Y) proteins, which bind AT-rich regions of the minor grove of DNA, and do not directly activate transcription but facilitate action of other factors such as NF-KB. It also has a region of homology to mammalian DNA methyl transferases, transcriptional activation, and repression domains, as well as a cysteine-rich region that forms three zinc fingers or plant homeodomains (PHD) (also called LAP for leukemia-associated protein domain).59 The PHD domain and the SET domain located at the carboxyl terminus are the regions most conserved with the Drosophila trx protein. The trx gene is required to maintain the proper expression of homeotic genes of the Bithorax and Antennapedia complexes in Drosophila.

mll has been targeted in mice by homologous recombination in ES cells to assess its role in development. mll heterozygous mice had retarded growth and displayed bidirectional homeotic transformation of the axial skeletion as well as sternal malformations. These mice also displayed hematopoietic abnormalities including anemia and decreased platelets, although morphology of the hematopoietic cells was normal, suggesting that mll haploinsufficiency on its own is inadequate for leukemic transformation. In contrast, mice with homozygous deletions die by embryonic day 10.5. Anterior boundaries of Hoxa-7 and Hoxc-9 expression were shifted posteriorly in heterozygous mice, whereas embryos with homozygous deficiency of mll failed to maintain expression of representative hox genes. Thus, mll positively regulates hox gene expression. hox genes, in general, are important determinants of the mammalian body plan and are also differentially expressed in subsets of hematopoietic cells. These data suggest that the mll gene is important for axial organization and hematopoietic differentiation.60 More recent studies have shown that mll and Bmi1 (a member of the polycomb family) have opposing functions. Mice that lack both genes develop normally.61

MLL is involved in translocations with at least 40 different partner genes, 19 of which have been cloned thus far (Fig. 6.4).3 In spite of the large size of the gene, the translocation breakpoints in MLL cluster around an 8.3-kb region just 5' of the PHD domain. The clustering of the breaks makes it possible to detect virtually all MLL rearrangements with a 0.74-kb cDNA probe on Southern blot analysis. The fusion genes that result consist of 5' MLL and 3' partner gene. The reciprocal fusion transcript (3' partner gene and 5' MLL) is also frequently expressed. The role of the partner genes in leukemogenesis has been the subject of much debate. The fact that they lack a common motif and are so varied suggests that they may be interchangeable and have only a minor role in leukemogenesis. However, the observation that the leukemia phenotype generated usually correlates with the specific MLL-partner gene fusion protein expressed argues against this hypothesis. For example, the more common MLL translocations include the t(4;11)(q21;q23), which generates the MLL-AF4 fusion and is found predominantly in 2 to 7% of all cases of ALL and more than 80% of lymphoblastic leukemia in infants. The t(11;19)(q23;p13.3) results in the MLL-ENL fusion transcript and is also found in ALL. In AML, the most common MLL rearrangements are the t(9;11)(q22q23) involving MLL and AF9, the t(6;11)(q27;q23) and the t(11;19) (q23;p13.1) involving MLL and ELL.3,4,54,62–64

Figure 6.4. The location of translocation breakpoints that involve MLL is indicated by colored bands.

Figure 6.4

The location of translocation breakpoints that involve MLL is indicated by colored bands. The involvement of MLL was determined by FISH, by Southern blot analysis or by RT-PCR. Symbols to the right of the band indicate that the translocation has been (more...)

Formal proof that the MLL/partner gene fusion products created by these translocations are important in hematologic malignancies has been provided by mll-af9 knock-in mice. The chimeric as well as heterozygous mice carrying the fusion gene developed AML. In contrast, mll-myc chimeras (carrying a truncated myc allele) did not develop leukemia. However, MLL-AF9 mice developed leukemia only after a latency period of over 2 months, suggesting that secondary mutations in other genes are necessary for overt malignant transformation.65

Other groups have also performed studies that reinforce the importance of the partner genes in leukemogenesis. MLL-ENL fusion cDNA when transduced by retroviral gene transfer into cell populations enriched in hematopoietic stem cells was capable of immortalizing early myelomonocytic cells. The immortalized cells as well as freshly infected bone marrow cells enriched for hematopoietic stem and progenitor cells were capable of inducing leukemias in 100% of recipients when transplanted into syngeneic recipients. In contrast, wild-type ENL or a deletion mutant of MLL-ENL lacking the ENL component did not demonstrate any in vitro transforming abilities.66

A two-hit model of oncogenesis has been proposed in which MLL translocations in humans simultaneously create an MLL fusion with a partner gene that could confer a gain-of-function activity, whereas MLL haploinsufficiency, due to loss of this normal functioning allele, would also contribute to the malignant phenotype.60,67 However, it is clear that alterations in other genes also are required.

Chromosomal Abnormalities Involving Transcriptional Co-activators

Transcriptional co-activators interact with the basal transcription machinery and with transcription factors such as the cAMP response element binding protein (CREB) and nuclear hormone receptors. Many of these co-activators also have histone acetyl transferase (HAT) activity, which is important in chromatin remodelling. A number of co-activators have recently been cloned at translocation breakpoints in leukemia. These include the CREB binding protein (CBP) gene, which is involved in both the t(11;16)(q23;p13.3) and the t(8;16)(p11;p13), which result in MLL/CBP and MOZ/CBP fusion transcripts, respectively.68–71 P300 located on chromosome 22 is a functional homologue of CBP and is involved in the t(11;22)(q23;q13), which gives rise to the MLL/P300 fusion transcript.72 Another co-activator that is potentially important in leukemogenesis is TIF2, which has been cloned in the inv(8)(p11q13) translocation that generates the MOZ/TIF2 fusion.73

CBP is one of the best studied of these co-activators to date. It is located on chromosome band 16p13.3, binds to the phosphorylated form of CREB, and also interacts directly with TFIIB and RNA polymerase II (basal transcription machinery). It functions as a global transcriptional co-activator by interacting with many DNA-binding transcription factors. These proteins are often discussed as CBP/P300 because they are functional homologues. Both have intrinsic HAT activity.74

Cloning of the t(8;16) led to the discovery of a novel gene MOZ and identification of CBP as its translocation partner. Patients with the t(8;16) are classified as AML-M4 patients or M5, with pronounced erythrophagocytosis by the blast cells in the majority of cases. Both AML de novo and t-AML cases have been reported. This is very similar to patients with inv(8) involving MOZ and TIF2 who also have AML-M5 with an erythrophagocytic picture.

In contrast to most patients with MLL translocations, almost all patients with t(11;16) involving MLL and CBP that have been reported to date have therapy-related leukemia, with a significant percentage having therapy-related myelodysplasia (t-MDS). CBP is also the gene responsible for the Rubinstein-Taybi syndrome in which loss of one functional allele results in a well-defined syndrome characterized by facial abnormalities, broad thumbs, and mental retardation, as well as the propensity for malignancy.75

Besides the CREB binding domain and HAT domain, the CBP protein also has other important domains, including the PHD domain found in many other proteins including MLL and some of MLL’s other partner genes (AF10, AF17). This domain is also present in trithorax and polycomb-like proteins in Drosophila, as well as in MOZ. The exact function of this domain is unknown, but it is postulated to be important in protein–protein interactions. CBP also contains a bromodomain, which is a motif that is conserved in humans, Drosophila (brahma), and the yeast SWI2/SNF2 complex. Several bromodomain-containing proteins including CBP, SWI2/SNF2, TAF250 and GCN5 are involved in transcriptional regulation as mediators or co-activators. Several of these proteins also have HAT activity, are present in large multi-protein complexes, and are important in chromatin modification. It has therefore been proposed that the bromodomain is important for protein–protein interaction, may influence the assembly or activity of these complexes, and may also be important in chromatin interaction.76 Recent structure–function studies of the HAT co-activator P/CAF(P300/CBP-associated factor) bromodomain showed that it interacts with acetylated lysine in a manner similar to the interaction of acetyl-CoA with histone acetyltransferases, suggesting that it may be important in regulation of HAT activity.77 CBP retains several of these domains, including the bromodomain and HAT domain (which includes the PHD domain) in the t(11;16). These domains have also been shown to be retained in the t(8;16).68,70

In summary, the exact mechanism by which these transcriptional co-activators contribute to leukemogenesis is unknown. Many of them have been postulated or demonstrated to have HAT activity.68,74 Chromatin remodelling through histone acetylation plays a major role in transcriptional activation by co-activators, and disruption of this process may be important in leukemogenesis.

Other Chromosomal Abnormalities

Gains and losses of a part of or whole chromosomes frequently occur in AML, both as solitary changes usually found at diagnosis or as additions in later disease stages. Most of the structural translocations occur in younger patients, with a median age in the thirties, whereas some of the numeric abnormalities and other structural rearrangements, such as –5 or loss of the long arm [del(5q)] or –7 or del(7q), occur in patients with a median age of over 50. Many of these latter patients have a history of working in environments that might have exposed them to mutagenic agents such as chemicals that include solvents, petroleum products, or pesticides.78,79 Secondary chromosome changes, such as del(20q), del(9p), and i(17q), occur in AML and also are associated with other diseases; these changes sometimes are found as the sole aberrations. Although it appears that CDKN2 (p16) may be the target for 9p21 deletion, despite intensive efforts the genes involved in other deletions such as 5q, 7q, and 20q are unknown. This has been a very difficult problem because there are no homozygous deletions and each of these is a very gene-rich region.80,81

Other Myeloproliferative Diseases

In polycythemia vera, an abnormal clone is present in about 15% of untreated patients. This number increases to 40% overall because the frequency with which abnormalities are seen is as high as 80% in the later phases of the disease.8 The five most common aberrations are, in descending order of frequency, 20q–, + 8, +9, gains of 1q and 13q–. Two-thirds of the cytogenetically abnormal cases have at least one of these aberrations.1 The presence of chromosomal abnormalities at diagnosis is not predictive of clinical outcome, but a change in karyotype, as with CML, is an ominous sign.8 In the terminal leukemic phase, –7 (20% of patients) and del(5q) (40%) have been observed. It is not clear whether these abnormalities are related to the therapy these patients may have received.

Approximately one-third of patients with agnogenic myeloid metaplasia have clonal abnormalities, commonly –7, 18, del(11q), or del(20q).1,8

Acute Myeloid Leukemia and Myelodysplastic Syndrome Associated with Prior Cytotoxic Therapy

One of the most serious consequences of successful treatment of a prior malignant disease is the occurrence of treatment-related myelodysplasia (t-MDS) or acute leukemia (t-AML).54,82,83 These patients have two different patterns of chromosomal abnormality, which are related to the type(s) of initial cytotoxic therapy. Patients who received alkylating agents, with or without radiation, often have MDS preceding AML, which on average occurs approximately 4 years after the start of therapy, and they show loss of chromosomes 5 and/or 7 or deletion of the long arm of chromosome 5 or 7. These patients often have very abnormal karyotypes, with deletions of 12p, 17p, and 20q as well. The response of these patients to antileukemic therapy often is very poor.

In contrast, with the increasing use of drugs that target topoisomerase II, such as the epipodophyllotoxins or anthracyclines, patients who have received these drugs often have balanced translocations, usually involving the MLL gene at 11q23 or, less often, the AML1 gene at 21q22.54 These leukemias may occur within less than a year of the beginning of therapy, lack an MDS phase, and may respond well to chemotherapy.54

Primary Myelodysplastic Syndrome

Cytogenetic analysis has provided several clues to the molecular pathogenesis of MDS. First, clonal chromosomal abnormalities have now been reported in more than 1800 patients with MDS, which is a heterogenous group of hematopoietic stem cell disorders 40 to 79% of whom have clonal abnormalities at diagnosis.2,8,84 Second, cytogenetic analysis provides prognostic information that can be incorporated into the clinical management of the disease. The aberrations most often associated with MDS include more than 15 structural rearrangements and 10 numeric changes. The common chromosomal abnormalities, +8, -5/del(5q), -7/del(7q), and del(20q), are similar to those seen in AML de novo, but some of the most characteristic AML-associated abnormalities such as t(8;21) in M2, t(15;17) in M3, or inv(16) in M4 are rarely seen in MDS.84 This suggests that patients with the specific types of AML that are associated with these abnormalities pass through a very brief, if any, preleukemic phase before leukemia develops. In general, unlike AML, the chromosomal changes do not show a close association with the specific subtypes of myelodysplastic syndrome; patients with complex karyotypes and abnormalities of chromosomes 5 and/or 7 have a poor prognosis.82 The exception is the “5q–” syndrome, in which there is an interstitial deletion of the long arm of 5. The syndrome occurs in a subset of older patients, frequently women, with refractory macrocytic anemia, generally low blast counts, and normal or elevated platelet counts.1,8 A number of growth factors and growth factor receptors have been localized to this region on chromosome 5q. Clearly, this region harbors a leukemia-suppressor gene. However, the search for this gene has been very slow because the region is large and very gene rich. Work of Le Beau and her colleagues have narrowed the region to 1 megabase on chromosome band 5q31.82 The loss of chromosome 7 also indicates that it too carries important genes that inhibit the development of leukemia. Le Beau et al. have defined two critical regions of deletion; the majority of patients have deletions of 7q22, whereas some have deletions of 7q32-33 instead.80

Malignant Lymphoproliferative Diseases

The chromosomal abnormalities in lymphoid disorders, especially in the non–Hodgkin’s lymphomas have been reviewed in considerable detail elsewhere.8,85–87 A high proportion of cases of lymphoma (79%) are characterized by recurring clonal chromosomal abnormalities; many of these abnormalities correlate with histologic and immunophenotypic subtypes (Tables 6.3A and 6.3B). Chromosome band 14q32 is frequently involved in B-cell lymphoma, whereas T-cell lymphomas are characterized by rearrangements that involve 14q11, 7q35, or 7p15, which are the bands containing the genes for the T-cell receptor a/d, b, or g chains, respectively.86,87 This section reviews the consistent translocations seen in Burkitt’s lymphoma, follicular lymphoma, chronic lymphocytic leukemia, B-cell acute lymphocytic leukemia (ALL), and in some T-cell disorders. Several of these neoplasms have specific genetic abnormalities that are part of the definition of the disease.

Table 6.3A. Cytogenic-Immunophenotypic Correlations in Malignant B-Lymphoid Diseases.

Table 6.3A

Cytogenic-Immunophenotypic Correlations in Malignant B-Lymphoid Diseases.

Table 6.3B. Cytogenetic-Immunophenotypic Correlations in Malignant T-Lymphoid Diseases.

Table 6.3B

Cytogenetic-Immunophenotypic Correlations in Malignant T-Lymphoid Diseases.


In 1972, Manolov and Manolova88 discovered that the malignant cells of patients with Burkitt’s lymphoma had an additional band at the end of the long arm of one chromosome 14. In 1976, Zech and colleagues89 first observed that the end of one chromosome 8 was consistently absent, and they suggested that the missing part was translocated to chromosome 14 [t(8;14)(q24;q32)]; 14q32 contains the immunoglobulin heavy chain gene (IGH). The t(8;14) also has been observed in nonendemic Burkitt’s tumors from America, Europe, and Japan. Thus, it is a highly characteristic chromosome anomaly in Burkitt’s lymphoma. This translocation also has been observed in other lymphomas, particularly those of the diffuse large-cell type.85 Two other related translocations were later identified in Burkitt’s tumors, and all three translocations involve chromosome 8 with a break in the same band, 8q24. One variant translocation involved chromosome 2 (locus of IGKappa) with a break in the short arm [t(2;8)(p12;q24)], and the other involved chromosome 22 with a break in the long arm in band 22q11 (locus of IGlamda). All three translocations have been identified in patients with B-cell ALL as well. The translocations result in inappropriate expression, either in level or timing of expression of the MYC gene, which is located on chromosome 8.90

Other recurring abnormalities in B-cell lymphoma include t(14;18)(q32;q21), t(11;14)(q13;q32), t(3;14)(q27;q32) and t(11;18) (q21;q21). The t(14;18)(q32;q21) is, in fact, the most common translocation in lymphoma (Fig. 6.5). This translocation was first identified by Fukuhara and colleagues in six of nine patients with poorly differentiated lymphocytic lymphoma, now called “malignant lymphoma, follicular, predominantly small cleaved cell” in the International Classification System.91 The correlation between karyotype and histology in 260 patients was reviewed at the Fifth IWCL.85 Among these patients, 15% had a normal karyotype. The karyotypic pattern varies greatly among the different subgroups and certain chromosomal abnormalities are virtually restricted to certain subtypes, for example, t(11;18) and MALT lymphoma and t(2;5) and anaplastic large-cell lymphoma.86 The t(14;18) is common in follicular low-grade lymphomas, whereas the t(8;14) is common in high-grade, small, non-cleaved-cell lymphomas. Occasionally, the t(14;18) is seen in lymphomas with a more aggressive, high-grade histology. Previous studies suggest that patients with diffuse large-cell lymphoma and a t(14;18) likely are older and have a poorer prognosis than those without this translocation. Of 102 patients with large-cell lymphoma, 19 had a t(14;18) and a rearrangement of the BCL2 gene located on chromosome 18. Their median disease-free survival was 33 months, whereas the median was not yet reached for the other patients without this rearrangement.92 Analysis of the karyotypic pattern in low-grade lymphomas also shows that certain additional chromosome changes, especially a gain of chromosome 7 or a deletion of the long arm of chromosome 6 [(del)6q] usually involving 6q15-6q24, appear to correlate with a more aggressive phenotype.86 The t(14;18) has been cloned, and breakpoints cluster in at least two sites on the BCL2 gene. The major cluster is in the 3’ untranslated region of the third exon.93 In the lymphoma cells, BCL2 gene is overexpressed. This leads to inappropriate expression of a structurally normal protein.94 Analysis of the function of BCL2 indicates that this gene is involved in programmed cell death (i.e., apoptosis). Its inappropriate expression because of the translocation prevents apoptosis and thus leads to a great increase in the number of B lymphocytes in tissues such as the lymph nodes and spleen.86 Additional genetic changes are required to transform these B cells to a fully malignant phenoytpe.

Figure 6.5. Partial karyotypes of trypsin-Giemsa-banded metaphase cells depicting nonrandom chromosomal rearrangements observed in lymphoid malignant diseases.

Figure 6.5

Partial karyotypes of trypsin-Giemsa-banded metaphase cells depicting nonrandom chromosomal rearrangements observed in lymphoid malignant diseases. (A) t(4;11)(q21;q23) in ALL; (B) t(1;19)(q21;p13) in pre-B cell ALL; (C) t(8;14)(q24;q32) in B-cell ALL (more...)

One of the most recent breakpoints to be cloned is the t(3;14)(q27;q32), in which IGH and a gene called BCL6 (or LAZ3) are involved.95 As with the t(8;14), the IGK and IGL loci can also participate in translocations. The break in BCL6 is usually within the first intron, which is fused to the immunoglobulin gene. Offit and colleagues96 used the appropriate probes to screen lymphoma samples from 102 patients with diffuse large-cell lymphoma for rearrangements of BCL2 and BCL6. BCL6 was rearranged in 23 cases, whereas BCL2 was rearranged in 21 cases. In a more recent study from this group of 215 patients with diffuse large-cell lymphoma, 110 had rearrangements of 14q32. Of these, 42 had t(14;18), 21 had t(3;14), and 33 patients had other genes involved in the rearrangement.97 Rearrangements of these two genes had prognostic significance because as in the earlier analysis, over 80% of patients with rearranged BCL6 and only 30% of those with rearranged BCL2 were projected to be free of disease progression at 36 months. The role of BCL6 in lymphomagenesis is unclear. It is expressed primarily in germinal center cells. Disruption of BCL6 in mice impairs development of germinal centers but the mice do not develop lymphomas.98

More recently, the importance of several other translocations has been appreciated.1,8 The t(11;14)(q13;q32) has been shown to be associated with B-cell chronic lymphocytic leukemia (CLL) as well as 30 to 50% of B-cell lymphomas that are classified as centrocytic lymphoma ( Kiel classification).99,100 These lymphomas have recently been grouped under an entity called mantle cell lymphoma (MCL).101 The malignant cells in MCL originate as a neoplastic expansion of the mantle zone around lymph node germinal centers, and the cells are intermediate in size between those of small lymphocytic and small–cleaved-cell lymphoma. It is now categorized as an intermediate-grade lymphoma because most patients tend to have a more aggresive clinical course (with median survival of 30 to 40 months in most series), compared with low-grade lymphoma.102 The breakpoint was originally cloned by Tsujimoto and colleagues,103 who called the locus at 11q13 BCL1. No gene was identified initially, but several other groups analyzing other genes found that one of the cyclins (CCND1), also called PRAD1 because it was isolated from a parathyroid adenoma breakpoint, was a partner in the translocation.104,105 The juxtaposition of the PRAD1 gene to the immunoglobulin heavy chain (IGH) gene results in overexpression of the cyclin D1 protein, which is crucial for cell cycle progression into the S phase. However, its oncogenic role in lymphoid tissue is unclear.

Another recurrent abnormality that has been described is the t(2;5)(p23;q35) in Ki-1-positive, anaplastic large-cell lymphoma.106 Patients with this abnormality have unique clinicomorphologic characteristics and a more favorable prognosis compared to other patients with large-cell lymphoma. The genes involved in this translocation are ALK, a protein tyrosine kinase at 2p23, and NPM1 (nuclear phosphoprotein or nuclearphosmin) at 5q35.86,107

Although the focus of this section has been primarily on translocations, the karyotypes of most lymphomas are very complex and include gains of chromosomes most often 7, X, and 12 and losses of 6 and the Y chromosome. Deletions of parts of chromosomes most often involve chromosome 1 both the short and long arms, chromosome 3 (short and long arms), 6q15, 6q21, 6q23-25, and 7q32.97 The genes that are the targets of these deletions are unknown.

In contrast to myeloid malignancies, where the creation of novel chimeric genes are the most commonly seen genetic abnormalities, activation of various cellular oncogenes seems to be the predominant molecular event observed in lymphoproliferative disorders. The activation of oncogenes may occur through somatic mutation, chromosomal translocation, or incorporation of viral oncogenes or viral enhancers of host oncogenes into the host genome. Detailed discussion of all oncogenes involved in the chromosomal aberrations implicated in lymphomagenesis is beyond the scope of this chapter. A brief discussion of the two best characterized and relatively common oncogenes implicated in lymphomagenesis, MYC and BCL-2, follows.

MYC gene, located on chromosome 8q24, is involved in translocations with multiple-partner genes encoding for the immunoglobulin genes as well as T-cell receptor genes described above. The normal function of the c-myc protein has not been fully elucidated, and the exact mechanism through which these translocations participate in lymphomagenesis is not well understood. However, the protein coding sequences of MYC gene participating in translocations are preserved, and it is believed that the tumorigenic activity of MYC is brought about by the quantitative changes in the level of expression or the timing of expression of the normal gene product. Overexpression or inappropriate expression of MYC protein causes maturation block and abnormal growth.108 however, the molecular events behind this specific effect are obscure. The transforming potential of MYC has been demonstrated in transgenic mice expressing myc fused to the IG enhancer. These mice initially developed polyclonal B-cell hyperplasia that progressed over a period of time to lethal lymphoid malignancies.

BCL2 is a gene that inhibits apoptosis and is located on chromosome 18q21. The most common translocation in NHL t(14;18) (q32;q21), found in 85% of follicular lymphomas, juxtaposes the BCL2 gene next to the IGH gene on 14q32. This juxtaposition on the der(18) chromosome results in altered BCL2 expression. Transgenic mice expressing BCL2 fused to the heavy chain gene uniformly developed lymphomas after a prolonged period of time, highly reminiscent of follicular lymphomas.109 The accumulation of malignant cells in these animals results from an extended lifespan of the malignant lymphocytes due to decreased cell death rather than increased proliferation. Thus, overexpression of BCL2 in murine models as well as in human tumors prevents apoptosis of affected cells.110 This, in turn, renders cells vulnerable for the acquisition of secondary genetic abnormalities, which are required for completion of the process of malignant transformation.

Chronic Lymphoproliferative Disorders

The one feature common to this diverse group of disorders is the malignant proliferation and accumulation in bone marrow and peripheral blood of relatively mature cells of the lymphocytic lineage. Although most run an indolent course, some subtypes run a rapid clinical course and carry a poor prognosis.

CLL is the most common leukemia in the U.S. and Europe, where it accounts for 30% of all cases, but it is extremely rare in the Orient. The early studies of cytogenetic pattern in CLL showed a normal karyotype in most samples. As better culture and banding methods have been applied to these studies, nonrandom clonal abnormalities have been detected in 40% to 100% of B-CLL. These include translocations involving 14q32, such as the t(11;14)(q13;q32) and t(14;19)(q32;q13), and trisomy for chromosome 12.1,8,99 The gene involved in the t(11;14) is CCND1 and that involved in the t(14;19) is the BCL3 gene.86,111 This proto-oncogene plays a central role in the NFKB regulatory pathway. In a large series of patients with CLL, clonal chromosomal changes were observed in 218 of 321 patients who could be examined cytogenetically.112 The most common abnormalities were trisomy 12 (67 patients) and structural abnormalities of chromosome band 13q14 (57 patients) and chromosome 14 (41 patients). This study showed that patients with normal karyotypes had a median overall survival of more than 15 years, compared with 7.7 years for patients with clonal changes. Patients with 14q aberrations also had a poorer prognosis.112 The information about T-CLL is still very limited.

Acute Lymphoblastic Leukemia

Cytogenetics and immunophenotyping are now considered integral parts of the diagnostic work-up for newly diagnosed patients with acute leukemias (see Table 6.3A). In addition, more sensitive molecular techniques including FISH and the polymerase chain reaction (PCR), which provide the ability to detect and monitor specific fusion gene products that arise as a result of reciprocal chromosome translocations, are very useful for assessing the clinical efficacy of treatment.

ALL is the most frequent leukemia in children. Patients who are between 3 and 7 years of age, with a white-blood-cell (WBC) count of less than 10,000/mL and whose leukemic cells express the common ALL antigen (CALLA+ or CD10+), have the best prognosis. The systematic efforts to identify poor-risk groups and then treat them aggressively, however, has continually improved the survival rate in these patients. It was rigorously demonstrated for the first time at the Third IWCL113 that the karyotype is an important independent prognostic factor in ALL. The Third IWCL found chromosome aberrations in 66% of the 330 patients (173 adults and 157 children) investigated.

The t(12;21)(p13;q22) that results in the TEL/AML1 fusion transcript is the most common gene rearrangement in childhood ALL, being found in about 25% of cases. It is a cryptic translocation detected only rarely by standard cytogenetics because of the similarity of the banding pattern, but easily detectable by molecular techniques such as FISH or RT-PCR. It was found in only 3% of adult ALL in retrospective studies. Leukemic cells exhibit a B cell precursor phenotype and patients have a good prognosis.114,115 TEL, which is also known as ETV6, is an ets-related transcription factor and is associated with almost 40 other genes at different translocation breakpoints (Fig. 6.6).3 The exact mechanism by which the TEL/AML1 fusion gene causes leukemia is unknown, but it is postulated to act as a dominant negative inhibitor of wild-type AML1 (CBFA) function.116

Figure 6.6. A map of the translocation breakpoints involving TEL determined primarily by FISH and less often by Southern blot or RT-PCR analysis.

Figure 6.6

A map of the translocation breakpoints involving TEL determined primarily by FISH and less often by Southern blot or RT-PCR analysis. Symbols to the right of the band indicate that the translocation has been cloned and the partner gene has been identified (more...)

Recent studies have suggested TEL’s possible role as a tumorsuppressor gene. In these studies, leukemic cells with one allele of TEL disrupted via the TEL-AML1 translocation were found to also have the other TEL allele deleted, abolishing all normal TEL function within the cells.117 However, mice lacking TEL demonstrate embryonic lethality.118 The role of TEL/AML1 in leukemia is the subject of ongoing studies. It is intriguing, however, that dysregulation of the same common pathway involving CBF, which is implicated in a significant number of patients with AML, also plays a central role in TEL/AML1 mediated leukemogenesis in ALL.

At the Sixth IWCL,119 29 of 172 adults with ALL (17%) and 9 of 157 children with ALL (6%) had the Ph chromosome, which is the most frequent rearrangement in adult ALL.120,121 At the cytogenetic level, breakpoints appear to be identical to those in CML. However, recent molecular analysis reveals that an important difference in the breakpoint site within BCR results in the formation of either a 210 kd protein (p210) that contains additional BCR sequences and is found in CML and some cases of ALL or a 190 kd protein (p190), which is found in the majority of patients with ALL.18,120 The p190 BCR/ABL appears to have stronger transforming activity in cell culture models compared with the p210 BCR/ABL.

In both adult and pediatric ALL, the presence of the BCR/ABL fusion transcript is associated with a poor prognosis, and its detection in leukemic cells has been useful in identifying patients who will require more intensive therapy, such as bone marrow transplantation (BMT) in first remission. Furthermore, studies of minimal residual disease by RT-PCR techniques have shown that the persistence of the BCR/ABL transcript following BMT is associated with a high risk of relapse.122

Another recurring chromosomal abnormality is the t(1;19)(q21;p13), which has been identified in approximately 25% of patients with a pre-B phenotype (cytoplasmic Ig+ and CALLA+).123 This breakpoint has been cloned using the probe for a transcription factor (E2A) located on chromosome 19.86,124 The translocation involves two genes that bind to DNA; the gene on chromosome 1 is called PBX. E2A is a basic helix-loop-helix transcription factor, whereas PBX is a homeobox protein. Transgenic mice expressing the E2A-PBX fusion gene develop malignant lymphoma.124

Of 216 patients with chromosomal abnormalities at the Third ICWL,113 18 (8.3%) had a t(4;11)(q21;q23) rearrangement. Fifty percent of these patients were children, most of whom were less than 1 year old. The association of t(4;11) with neonatal or early childhood ALL is particularly interesting in view of the low incidence of ALL in this age group; acute leukemias in this group usually are of the myeloid type and, as noted earlier, they usually involve the MLL gene.63 The t(4;11) results in the MLL/AF4 fusion transcript, which is readily detectable by RT-PCR.56,126 Leukemic cells frequently exhibit biphenotypic features including expression of myeloid markers such as CD15, and patients present with other factors such as hyperleucocytosis, which have been independently associated with a poor prognosis. The breakpoint in MLL in this fusion is similar to that in translocations associated with myeloid leukemias, pointing to the importance of the partner gene in the phenotype of these leukemias.

Other chromosomal abnormalities associated with ALL that have been useful in risk stratification include hyperdiploidy, that is, cells with more than 50 chromosomes, which is associated with a good prognosis, in contrast to patients with hypodiploidy who have a poor prognosis.120,123

Chromosome losses or deletions are less frequent, and the regions involve 6q, 9p, 11q, and 12p. Deletions of 9p occur in approximately 20% of ALL cases. Homozygous deletions of DNA sequences on 9p, which include the IFN gene cluster, methylthioadenosine phosphorylase (MTAP), CDKN2 [p16INK4A, MTSI], and CDKN2B, have now been described in the majority of ALL cases with 9p loss.127,128 Some recent studies found homozygous deletions of p16 occuring in as many as 30% of B lineage ALL cases and 95% of T lineage cases.129

The three translocations described for Burkitt’s lymphoma are seen also in B-cell ALL. Regarding karyotype and age, patients with a deletion of 6q and a modal chromosome number greater than 50 were younger and those with a Ph chromosome or a 14q11 were older than patients with other abnormalities. In summary, the highest remission rates were in patients with a normal karyotype and a modal number greater than 50; the lowest rates were seen in patients with a Ph chromosome, 14q11 chromosome, t(8;14), and t(4;11).119,121,123

T-Cell Disorders

Although fewer leukemias of T-cell origin have been studied, a distinct pattern of nonrandom karyotypic abnormalities is emerging. Rearrangements involving the proximal bands of chromosome 14 (14q11-q13) are relatively common, and those involving two regions of chromosome 7 (7q35 and 7p15) also occur in T-cell malignancies but have been observed in nonmalignant T-cell disorders as well. Breaks involving these regions are very rare in other malignant diseases (see Table 6.3B). One recurring rearrangement in T-cell neoplasia, particularly CLL, is a paracentric inversion of chromosome 14 with a proximal breakpoint at q11 and a distal breakpoint at q32 [inv(14)(q11q32)].130 A closely related rearrangement, t(14;14)(q11;q32), is seen in T-cell neoplasia and in phytohemagglutinin-stimulated lymphocytes from patients with ataxia-telangiectasia (A-T), as well as in the leukemic cells of A-T patients in whom this disease evolved.131 A number of reports from Japan have described the frequent occurrence of 14q11 breaks in adult patients with T-cell leukemia-lymphoma patients.131,132 Williams and associates134 have described a t(11;14)(p13;q13) in the leukemic cells of 4 of 16 patients with T-cell ALL; the breakpoint was later shown to be 14q11. Data confirm the observation made some time ago that the proximal region of chromosome 14 was important in T-cell neoplasia.135 Analysis of these 14q11 translocations with molecular probes has shown that the T-cell receptor α- or d-chain (TCRA or D) locus is involved.136 One of the first translocations to be cloned in T-cell leukemias was the t(8;14)(q24;q11). In this translocation, the breakpoint also involves MYC at 8q24, but the other gene is TCRA. Shima and colleagues136a have shown that the break in MYC is 3' of the third exon and MYC remains on chromosome 8; in TCRA, the break is just 5' of a Ja segment (JaD). This translocation is similar to these involving the immunoglobulin light-chain gene, in which MYC also remains on chromosome 8. TCRA also is involved with translocations affecting 14q32 and the heavy chain gene in the inv (14).

Another translocation of special interest is the t(1;14)(p32;q11). The translocation juxtaposes the TAL1 gene (also called SCL) with the TCRD, and it occurs in approximately 3% of patients with T-ALL.137,138 Using probes for TAL1, several groups showed that there is a 90-kb deletion involving the 5' region of the TAL1 gene in up to 25% of patients.139 TAL1 is not expressed in lymphoid cells, and the translocation or deletion results in its inappropriate expression in these cells. More recently, analysis of mRNA from T-ALL samples has revealed ectopic expression of TAL1 in 35% of patients whose cells have neither a translocation or a deletion. Thus, TAL1 is expressed in over 60% of patients with T-ALL, which makes it a very critical gene in this leukemia.137 More detailed analysis of rearrangements of 7q in T-cell disorders has revealed that some patients have breaks at 7q34 to 7q35, the location of the β-chain for the T-cell receptor (TCRB).87,140 Rearrangements rarely affect TCRG at 7p15.

Solid Tumors

Although solid tumors, carcinomas in particular, play a much larger part in human neoplasia than hematologic malignancies, much less is known about the cytogenetic abnormalities that characterize them. Among the reasons for this discrepancy is, first, the difficulty of obtaining successful chromosome preparations from solid tumors because of the extensive fibrosis or necrosis that frequently is associated with these tumors. Second, until recently, many investigators questioned the relevance of the chromosome changes in malignant cells; therefore, this difficult area of research was not pursued. Third, the karyotypes of the tumor cells frequently show high modal numbers, often 60 to 90 chromosomes, with many bizarre marker chromosomes. Therefore, it is difficult to distinguish the primary change from those related to secondary evolution with progression of the malignant phenotype because most studies have involved highly advanced, often metastatic lesions.

With newer culturing and banding techniques, patterns of relevant and consistent chromosomal rearrangements are emerging. During the last 10 years, the number of reported cytogenetic abnormalities in solid tumors has risen dramatically, as is illustrated by the recent Catalog of Chromosome Aberrations in Cancer, and Cancer Chromosome Aberration Project ( Moreover, cytogenetic analyses have demonstrated the association of specific chromosomal changes with particular types of solid tumors, most especially mesenchymal tumors (Tables 6.4A and 6.4B). The genes involved in some of these breakpoints have been cloned. Overall, the number of cytogenetically characterized solid tumors is still small compared with leukemias and lymphomas.1,2,6,141 The number of specific chromosomal abnormalities that have been characterized by molecular studies also is much smaller compared with translocation breakpoints in leukemia and lymphoma.142 We are certain that the next few years will see a dramatic increase in the molecular characterization of cytogenetically detected abnormalities in solid tumors. Applications of techniques such as CGH, FISH, SKY, and molecular genetic analyses of loss of allelic heterozygosity (LOH) have contributed new knowledge to our understanding of the genetic changes that characterize solid tumors.11,142–144 For this review of karyotypes in solid tumors, two broad groups of benign and malignant neoplasms are identified; each group is then divided into six categories: (a) epithelial, (b) mesenchymal, (c) neurogenic, (d) germ cell, (e) embryonal tumors, and (f) tumors of unknown histogenesis.

Table 6.4A. Nonrandom Chromosome Abnormalities in Solid Tumors.

Table 6.4A

Nonrandom Chromosome Abnormalities in Solid Tumors.

Table 6.4B. Nonrandom Chromosomal Abnormalities in Solid Tumors.

Table 6.4B

Nonrandom Chromosomal Abnormalities in Solid Tumors.

Benign Tumors

Although much of the discussion in this chapter implies that chromosomal aberrations are equivalent to a malignant phenotype, there are a number of exceptions in solid tumors. In myeloproliferative disorders, patients with clonal chromosomal abnormalities in marrow cells have been observed for up to 12 to 15 years without undergoing leukemic transformation. Several benign tumors have clonal abnormalities of which the meningiomas described by Mark and colleagues145,146 and by Zankl and Zang147 have been studied most extensively. However, there are now numerous reports of clonal cytogenetic abnormalities in other benign solid tumors.147,148 Moreover, apparently normal fibroblasts in tumors have been shown to contain an extra chromosome 7; this chromosome carries the epithelial growth factor receptor and the MET oncogene.149

Epithelial Tumors

Salivary Gland Tumors

More than 200 cases with clonal karyotypic aberrations have been reported. Mark and associates150 first reported clonal chromosome abnormalities in approximately 47 of 100 parotid gland tumors examined. Of 47 adenomas with abnormal karyotypes, 34 had involvement of one of three particular chromosome regions: 8q12, 12q13-15, and 3p21. A t(3;8)(p21;q12) was the most common abnormality, occurring in 27% of cases. A t(11;19)(q21;p13) has been described in adenolymphoma (i.e., Warthin’s tumor). These abnormalities have not been reported in the few cases of malignant salivary gland tumors studied so far. Recently, the t(3;8)(p21;q12) in pleomorphic adenomas has been shown to result in promoter swapping between PLAG1, a novel, developmentally regulated zinc finger gene at 8q12, and the constitutively expressed gene for beta-catenin (CTNNB1), a protein interface functioning in the WG/WNT signalling pathway and specification of cell fate during embryogenesis. Fusions occur in the 5'-noncoding regions of both genes, exchanging regulatory control elements while preserving the coding sequences. Due to the t(3;8)(p21;q12), PLAG1 is activated and expression levels of CTNNB1 are reduced. Activation of PLAG1 has also been observed in an adenoma with a variant translocation t(8;15)(q12;q14). These observations indicate that PLAG1 activation due to promoter swapping is a crucial event in salivary gland tumourigenesis (Kas).151

Colonic Adenomas

Trisomies for chromosomes 7, 8, 13, and 14 have been identified in a few cases reported thus far.1,152 Trisomy 13 has been reported in 38% of cases. Other recurring abnormalities are del(1)(p36) and del(8p). By using DNA probes, loss of heterozygosity for markers on chromosome arm 5q has been reported in 20 to 50% of colorectal carcinoma and in approximately 30% of patients with sporadic colonic adenomas.153 The APC gene responsible for familial adenomatous polyposis was cloned from the long arm of chromosome 5 (band 5q21).154

Benign Ovarian Tumors

Trisomy 12 has been reported as the sole abnormality in five benign ovarian tumors (thecoma or fibroma), and two other tumors had trisomy 12 in addition to other abnormalities.155 Thus, seven of nine cytogenetically abnormal benign ovarian neoplasms are characterized by this trisomy. The high frequency of trisomy 12 in benign ovarian tumors, often as the sole abnormality, suggests that it may be a primary karyotypic event in the initiation of these tumors. Monosomy 22 has also been reported in two ovarian granulosa cell tumors.156

Mesenchymal Tumors

Uterine Leiomyomas

The most common chromosomal aberrations in uterine leiomyomas are t(12;14)(q13-15;q23-24), del(7)(q21.2q31.2), trisomy 12, and rearrangements of 6p. It appears that breaks in 14q22-24 and in 12q14-15 are the most common abnormalities.148,157,158 An identical translocation, t(12;14)(q13-15;q23-24), was found as the only abnormality in 4 of 34 leiomyomas.157 Other abnormalities seen in leiomyomas include rearrangements of 6p, del(7)(q21.2q31.2), and rearrangements of 1p36. Endometrial polyps also have been reported with rearrangements of 6p21 and 12q13-14.158


Interestingly, the database on benign and malignant tumors of adipose tissues is relatively extensive. More than 200 cytogenetically abnormal lipomas have been reported and only about 20 to 25% of all lipogenic tumors (lipomas, angiolipomas, spindle cell lipomas, and atypical lipomas) examined had no detectable abnomalities.7 Of 26 lipomas karyotyped, 70% had consistent chromosome rearrangements, and 13 of them had a reciprocal translocation involving 12q13-15.1 This breakpoint also has been observed in liposarcomas. Analysis of 91 other cases allowed a classification of lipomas into four cytogenetic subgroups: (a) those with normal karyotypes, (b) those with hyperdiploidy with ring chromosomes, (c) those with pseudodiploidy and rearrangement of 12(q13-15), and (d) those with hypodiploid or pseudodiploid karyotypes and other aberrations.159,160 The region of chromosome 12 band q13-15 has now been observed to be involved in lipomas, liposarcomas, leiomyomas, and mixed salivary gland tumors. Mrozek and colleagues148 showed that chromosome 12 breakpoints are cytogenetically different in benign and malignant tumors. The molecular mechanism involved in abnormalities of this region has been elucidated in myxoid liposarcoma, but the breakpoint in lipomas appears to be different from the liposarcomas. The t(12;16) and fusion of the CHOP gene at 12q13 to the FUS gene on chromosome 16 is characteristic of myxoid liposarcomas and is useful diagnostically in distinguishing them from lipomas.161 The gene involved in lipomas has been identified as HMGI-C at 12q15 (Petit), an architectural factor that functions in transcriptional regulation.162–164 HMGI-C DNA-binding domains (AT hook motifs) are translocated to either a LIM or an acidic transactivation domain in the fusion partner genes. Multiple chromosomes have been found as the translocation partners of chromosome 12 but 3q27-q28 is preferentially involved. Other partners include LPP (lipoma preferred partner gene) on 3q27 and LHFP (lipoma HMGIC fusion partner), which acts as a translocation partner of HMGIC in a lipoma with t(12;13).162–164

Neurogenic Tumors


This is the best characterized benign solid tumor. Zankl and colleagues147 first described a loss of one chromosome 22 in meningioma in 1970. Monosomy 22 or del(22)(q12.3) has now been reported in approximately 70% of cases or 95% of tumors with abnormal karyotypes.145 The NF2 gene has been identified as the critical gene involved in this chromosomal region.165 Secondary chromosomal changes include rearrangements of chromosomes 1 (loss of 1p), 8 (loss of one copy), and 14 (loss of one copy) and the X and Y chromosomes.

Neurilemomas also have been reported to show monosomy 22 and involvement of NF2.

Other benign tumors with recurrent chromosomal alterations include chordoma, osteochondroma, and pulmonary hamartoma as listed in Table 6.4A.

Malignant Tumors

Malignant tumors with recurrent chromosomal alterations are listed in Table 6.4B.

Lung Cancer

Karyotypic studies have revealed multiple cytogenetic changes in most small-cell lung carcinomas (SCLCs) and non–small-cell lung carcinomas (NSCLCs). Nearly all small cell lung cancers have a deletion of the short arm of chromosome 3 as one of the aberrations in a complex karyotype. NSCLCs also have a del(3p) as well as other anomalies. In SCLCs, losses of 3p, 5q, 13q, and 17p predominate; double minutes associated with amplification of members of the MYC oncogene family may be common late in the disease.166,167 In NSCLCs, deletions of 3p, 9p, and 17p, +7, i(5)(p10), and i(8)(q10) often are reported. The recurrent deletions encompass sites of tumor-suppressor genes commonly inactivated in lung carcinomas, such as CDKN2A (9p21), RB1 (13q14), and TP53 (17p13). Despite technical advances in cell culture, the rate of successful karyotypic analysis of lung carcinomas has remained low. Alternative molecular cytogenetic methods to assess chromosome changes in lung cancer, particularly comparative genomic hybridization (CGH) analysis, have yielded new insights. Initial CGH studies confirm the existence of many of the karyotypic imbalances identified earlier in lung cancer and have revealed several new recurrent abnormalities, such as 10q– in SCLC, that had not been recognized previously.166 In the future, application of molecular cytogenetic approaches, such as SKY will enable investigators to define more precisely the spectrum and clinical implications of chromosome alterations in lung cancer.

Whang-Peng and co-workers168 first reported a specific chromosome abnormality in SCLC. Specimens from 25 patients were successfully studied, including 1 tumor specimen, 2 pleural effusions, 8 metastatic bone marrow cells, and 16 long-term SCLC cell lines. At least one chromosome 3 in all metaphases examined had a deletion of the short arm. The shortest region of overlap in all deletions was band 3p14 to p23. In their study, this abnormality was not detected in any of the NSCLC cell lines. Other investigators have since confirmed this observation but have failed to see del(3p) in every SCLC. Moreover, Zech and associates have also reported this abnormality in all four subtypes of lung cancer.167 In addition, molecular analysis of lung cancer cells has shown that loss of heterozygosity for markers on chromosome arm 3p occurs consistently in SCLC and occasionally in NSCLC.168,169 The 3p region has been the focus of intense search for putative tumor-suppressor genes.170–172 Candidate genes on 3p include the von Hippel-Lindau (VHL) gene at 3p25, the ubiquitin-activating enzyme homologue (UBE1L) at 3p21, the genes for the dinucleoside polyphosphate hydrolase FHIT, and receptor protein-tyrosine phosphatase gamma PTPRG at 3p14.2. A region of homozygous deletion on 3p21.3 has been described in a breast cancer cell line that overlaps previously described deletions in SCLC.172 Cloning and sequencing of the breakpoint demonstrated that the homozygous deletion resulted from an interstitial deletion and significantly narrows the minimum common deleted region on 3p to 120 kb.170 These data suggest the presence of multiple tumor-suppressor genes on because this region is distinct from a previously reported region that suppresses tumor formation of the murine A9 fibrosarcoma cells.173

Lukeis and colleagues174 first reported 9p abnormalities in 9 of 10 lung cancers they examined. These included five adenocarcinomas, three squamous, and two large-cell carcinomas. Nonreciprocal translocations, deletions, or chromosome loss resulting in loss of material from the short arm of chromosome 9 with breakpoints in the region 9p11-p14 were observed. Thus, loss of genetic material from 9p also may contribute to the malignant process in these tumors. CDKN2 (p16INK4A), which is a gene involved in regulation of the cell cycle, recently was shown to be homozygously deleted in a significant percentage of lung cancer cell lines.174 Otterson and colleagues175 demonstrated that only 6 of 55 SCLC samples (11%) had lost p16 protein, and all six belonged to the rare subset of SCLC with wild-type RB expression. Conversely, of 48 SCLC samples with no or mutant RB, all showed detectable levels of p16 protein. In contrast, 23 of 33 of NSCLC samples (70%) had loss of p16. Twenty-two of 26 NSCL lines with wild-type RB had no p16, whereas six of seven NSCL lines with no or mutant RB had detectable p16. The inverse correlation of RB and p16 expression and the absence of p16 inactivation in RB-SCLC lines (0 of 48) confirms a common p16/RB growth suppressor pathway in human lung cancer. Whether one or several other commonly deleted genes on the short arm of chromosome 9 is involved in the malignant process in lung cancer is still unclear.174–177

Head and Neck Cancer

Recurrent cytogenetic abnormalities in squamous cell carcinomas of the head and neck region have recently been described. The most frequent changes were deletions. Losses affecting 3p13-p24, 5q12-q23, 8p22-p23, 9p21-p24, and 18q22-q23 ranged in frequency from 40 to 60% of tumors. There was gain of 3q21-qter, 5p,7p,8q, and 11q13-q23 in 28 to 38% of tumors.178,179 Gain of material of 11q13 is postulated to be associated with amplification of the CCNDI/PRADI gene at that locus.

Comparative genomic hybridization (CGH) has been performed on primary head and neck squamous cell carcinomas (HNSCC) to discover molecular genetic alterations underlying the progression of these tumors. Prevalent changes observed in more than 50% of the HNSCC analyzed include deletions of chromosomes 1p, 4, 5q, 6q, 8p, 9p, 11, 13q, 18q, and 21q and DNA over-representations of 11q13 as well as 3q, 8q, 16p, 17q, 19, 20q, and 22q. The calculation of ratio profiles of tumor subgroups revealed that well-differentiated carcinomas (G1) were defined by the deletions of chromosomes 3p, 5q, and 9p together with the over-representation of 3q, suggesting the association with early tumor development. Accordingly, the undifferentiated tumors (G3) were characterized by additional deletions of chromosomes 4q, 8p, 11q, 13q, 18q, 21q, and over-representations of 1p, 11q13, 19, and 22q. Thus, CGH patterns of chromosomal imbalances may help to define the consistent genetic alterations that characterize head and neck squamous cell carcinomas.179

Renal Cell Carcinoma

A constitutional t(3;8)(p21;q24) was observed in the lymphocytes of 10 affected members of a family among whom bilateral renal carcinoma segregated in an apparently autosomal dominant fashion.180,181 Other families with renal cell carcinoma and breakpoints in 3p were subsequently described, leading to the identification of a gene named HRCA1 immediately adjacent to the breakpoint on 3p. In addition, deletions or structural rearrangements of the short arm of chromosome 3 with breakpoints in bands 3p11-p21 are the changes most consistently seen in sporadic renal cell carcinoma.182 3p deletion may be found as the sole abnormality in some cases, as well as in all cells showing clonal abnormalities.1,6,182 These observations suggest that del(3p) may be a primary event in the development of renal cell carcinoma. In fact, three distinct regions of 3p appear relevant to renal cell cancer development.

The VHL syndrome was mapped to 3p25-26 on the basis of studies of 28 pedigrees comprising 164 affected persons.183 Mutations of the VHL syndrome gene, which maps to 3p25-26, have been shown to predispose to sporadic kidney cancer as well as kidney cancer in families.184 The VHL gene is mutated in a high percentage of clear-cell renal carcinomas, whereas it is not mutated in papillary renal cancer, thus suggesting a fundamental genetic difference between papillary and nonpapillary renal carcinoma.185

Although the great majority of the more common nonpapillary renal cell carcinomas have cytogenetically visible loss of material from the short arm of chromosome 3, other recurring chromosomal abnormalities that have been described in nonpapillary kidney cancer are t(3;5)(p13;q22), and rearrangements of 5q22-35. Papillary carcinomas have +7 in 56% and t(X;1)(p11.2;q21) in 20% of cases.142

Breast Cancer

More than 400 breast carcinomas with clonal karyotypic abnormalities characterized by banding techniques have been reported by Mitelman.1,7 Both complex and simple karyotypic changes have been reported. The two most common rearrangements are i(1q) and der(1q;16p), which were detected in approximately 40% of near diploid and hyperdiploid tumors. Further rearrangements or other derivatives from chromosome 1 also were frequently observed (i.e., approximately 20% of cases). Other recurrent abnormalities include +7, +8, and +20. Der(1;16)(q10;p10) and del(3p) are other abnormalities seen in benign fibroadenomas, fibrocystic disease, and carcinomas. In a recent study comparing chromosomal alterations in primary breast cancer to those in metastatic cancer,186,187 random numeric changes were seen in the primary cancers, whereas structural alterations, homogenous-staining regions, and double minutes were more commonly observed in the metastatic tumors. Chromosome 1 was significantly involved in nonrandom abnormalities in both primary and metastatic cases.

Studies at the DNA level have revealed multiple chromosomal regions with amplification in breast cancer. The most intensely studied is the ERBB2 gene, which is located on 17q11-12 and is amplified in 20 to 30% of breast cancers,188 Other amplicons map to 11q13, 20q13 or involve the MYC gene on 8q24 or ZNF217 and NABC1 on 20q.189 Using CGH on 55 unselected primary breast carcinomas, gains of 1q (67%) and 8q (49%) were the most frequent aberrations. Other recurrent gains were found at 33 chromosomal regions, with 16p, 5p12-14, 19q, 11q13-14, 17q12, 17q22-24, 19p, and 20q13 being most often (>18%) involved. Losses found in >18% of the tumors involved 8p, 16q, 13q, 17p, 9p, Xq, 6q, 11q, and 18q. The total number of aberrations per tumor was highest in poorly differentiated and aneuploid tumors. The high frequency of 1q gains and presence of +1q as the sole abnormality suggest that it is an early genetic event in breast cancers. In contrast, gains of 8q were most common in genetically and phenotypically advanced breast cancers. The vast majority of breast cancers (80%) have gains of 1q, 8q, or both and three changes (+1q, +8q, or -13q) account for 91% of the tumors.190

Colorectal Carcinomas

Both simple and complex karyotypes have been detected in colorectal adenocarcinomas. Frequently recurring changes have been i(8q), i(13q), del(1)(p22), i(17q), and i(1q). The most common numeric aberrations have been gains of chromosomes 7, 13, and X and losses of Y, 18, 14, 21, 4, 8, and 15. The principal imbalances resulting from the structural rearrangements seem to be gains of material from chromosome arms 8q, 13q, 17q, and 1q and loss from 1p, 8p, 13p, and 17p.2 The most common changes include structural rearrangements of chromosomes 1 and 17 as well as trisomy 7 and trisomy 12.1,2,6 Loss of a chromosome 5 allele was reported by Solomon and colleagues.153

Reports of loss of material from the short arm of chromosome 17 and long arm of chromosome 18 prompted molecular geneticists to look at these chromosomes using DNA probes. The most detailed molecular study of colorectal carcinomas was by Vogelstein and co-workers,191 who demonstrated that the progressive accumulation of genetic changes parallels the clinical progression of colorectal tumors from normal epithelium to benign tumors and, further, to the malignant stage of the disease. By molecular analysis, loss of heterozygosity for DNA sequences from chromosome regions 5q, 17p, and 18q were found to occur in a high percentage of colorectal carcinomas.191,192 Vogelstein et al. proposed that colorectal tumorigenesis proceeds through a series of genetic alterations involving oncogenes (RAS) and tumor-suppressor genes APC on 5q, TP53 on 17p, and DCC on 18q.191 Hemizygous deletions of chromosome arms 17p and 18q usually occur at a later stage of tumorigenesis than deletions of 5q or RAS gene mutations. Accumulation of these genetic alterations rather than the order in which they occur appears to be most important in colorectal tumorigenesis.

The DCC gene was identified from a segment of chromosome 18q, and it has been shown to be mutated in a few colorectal carcinomas.192 In addition, a minimally deleted region on chromosome 18q21, which includes DPC4/SMAD4 and DCC, has been defined. There appears to be significant genetic heterogeneity, with DPC4/SMAD4 the deletion target in up to a third of the cases and DCC or a neighboring gene the target in the remaining tumors.193 It has long been speculated that 5q deletions in colorectal carcinomas represent an inherited cancer predisposition gene, particularly in families with preceding polyposis.194 Two genes, MCC (mutated in colon cancer) and APC (adenomatosis polyposis coli), have been identified in the 5q21 chromosomal region.154 APC is mutated in the germline of some patients with familial adenomatous polyposis (FAP) and Gardner’s syndrome.

Other chromosomal loci also have been identified as being mutated in families with nonpolyposis colon cancer (HNPCC). These loci are located on the short arm of chromosome 2 (MSH2), short arm of chromosome 3 (MLH1), and on chromosome 7 (PMS1 and PMS2). These chromosomal regions are not associated with loss of material in colon cancer, but the genes are important in the repair of replication errors.195–197 Tumors arising in patients with HNPCC exhibit somatic mutations of the same genes that are involved in colorectal tumorigenesis in the general population (e.g., RAS, APC). In addition, these tumors are characterized by a marked instability of repeated sequences throughout the genome. This instability results from an absence of DNA mismatch repair, which has been traced to inactivating germline mutations in one of the four human homologues of bacterial mismatch repair genes listed earlier.197 Of families with HNPCC, 76% have been shown to have germline mutations in one (or several) of these genes.

Comparative genomic hybridization (CGH) has been used to detect amplified and/or deleted chromosomal regions in colorectal tumors. In one study, 45 sporadic colorectal carcinomas were screened for chromosomal aberrations using direct CGH. The median number of chromosomal aberrations per tumor was 7.0 (range 0–19).143 Gains of 20q (67%) and losses of 18q (49%) were the most frequent aberrations. Other recurrent gains of 5p, 6p, 7, 8q, 13q, 17q, 19, and X and losses of 1p, 3p, 4, 5q, 6q, 8p, 9p, 10, 15q, and 17p were found in >10% of colorectal tumors. High-level gains (ratio >1.5) were seen only on 8q, 13q, 20, and X and only in aneuploid tumors. Aneuploid tumors had significantly more chromosomal aberrations (median number per tumor of 9.0) compared to diploid tumors (median of 1.0) (p < .0001). The median numbers of aberrations seen in DNA hyperdiploid and highly aneuploid tumors were not significantly different (8.5 and 11.0, respectively; p = .58). Four tumors had no detectable chromosomal aberrations and these had the diploid amount of DNA. A higher percentage of tumors from male patients showed Xq gain and 18q loss compared to tumors from female patients (p = .05 and .01, respectively). High tumor S phase fractions were associated with gain of 20q13 (p = .03), and low tumor apoptotic indices were associated with loss of 4q (p = .05). Tumors with TP53 mutations had more aberrations (median of 9.0 per tumor) compared to those without (median of 2.0) (p = .002), and gain of 8q23-24 and loss of 18qcen-21 were significantly associated with TP53 mutations (p = .04 and .02, respectively). Dukes’ C/D stage tumors tended to have a higher number of aberrations per tumor (median of 10.0) compared to Dukes’ B tumors (median of 3.0) (p = .06). The low number of aberrations observed in apparently diploid tumors compared to aneuploid tumors suggests that genomic instability and possible growth advantages in diploid tumors do not result from acquisition of gross chromosomal aberrations but rather from selection for other types of mutations.143

In a second study, nine colorectal adenomas and 14 carcinomas were analyzed by CGH, and DNA ploidy was assessed with both flow and image cytometry. In the nine adenomas analyzed, an average of 6.6 (range 1–11) chromosomal aberrations were identified. In the 14 carcinomas, an average of 11.9 (range 5–17) events were found per tumor. In the adenomas, the number of gains and losses was balanced (3.6 vs 3.0), whereas in carcinomas, gains occurred more often than losses (8.2 vs 3.7). Frequent gains involved 13q, 7p, 8q, and 20q, whereas losses most often occurred at 18q, 4q, and 8p. These data suggest that the difference between chromosomal aberrations in colorectal adenomas and carcinomas, as detected by CGH, is an increased number of chromosomal gains that show a nonrandom distribution. Gains of 13q and also of 20q and 8q especially seem to be involved in the progression of adenomas to carcinomas.144

Bladder Cancer

Several studies of chromosomal abnormalities in bladder cancer have reported structural rearrangements of chromosomes 1, 5, and 11, as well as numeric aberrations involving chromosomes 7 and 9.1,198 Monosomy 9 has been reported in 8 of 19 bladder tumors, one of which had monosomy 9 as the sole abnormality.198 Isochromosome 5p (i[5p]) has been reported in 20% of all bladder tumors, whereas several copies of a chromosome 5 were deleted in a few cases. This may have the same effect as an isochromosome of 5p. Thus, isochromosome 5p or del(5q) may be important in this tumor.198 The same commonly deleted region on 9p21 has been identified in bladder cancer as in other tumor types; however, it is not clear if CDKN2 represents the only target of the chromosome 9 deletions in bladder cancer.177

Malignant Mesenchymal Tumors

Several key advances have been made during the last few years in this group of tumors. Mesenchymal tumors are relatively rare, accounting for less than 1% of all human neoplasms. They are very heterogeneous, however, and may present diagnostic problems.1,199 Recently, cytogenetic and molecular analysis of malignant (i.e., sarcoma) and benign forms of these tumors yielded some very important clues regarding the heretofore unsuspected relationship of some of these rare neoplasms, and provided help in classifying some of the undifferentiated forms of these tumors. Moreover, that the benign and malignant forms have related karyotypic changes provides an important resource for identifying the additional genetic changes that occur in the malignant compared with the benign form. In fact, the molecular biology of soft-tissue sarcomas has provided the perfect example of how cytogenetic and molecular approaches can contribute toward a clearer understanding of the development of soft-tissue sarcomas.


Recurring translocations have been described in both liposarcoma and synovial sarcoma.1,200,201 A t(12;16)(q13;p11) has been described, but only in the myxoid subgroup of liposarcomas, whereas other abnormalities, including ring chromosomes, appeared to be more frequent in well-differentiated sarcomas. As discussed previously, a breakpoint cluster region on chromosome 12q13-15 is shared by both lipomas and myxoid liposarcomas.148,201 Mrozek and colleagues148 recently provided evidence that the chromosome 12 breakpoints are cytogenetically different in benign and malignant lipogenic tumors. In their study, two malignant liposarcomas, one myxoid and one mixed liposarcoma, were described with t(12;16) as the sole abnormality. The breakpoints in both instances were sublocalized to bands 12q13.3 and 16p11.2. Also, in this same study, four cases of lipomas were characterized by structural rearrangements of chromosome 12. In all four cases, the chromosome 12 breakpoint could be unequivocally assigned to band q15, although the rearrangements involved different partner chromosomes.

A candidate gene called CHOP or human GADD153 maps to the breakpoint region at 12q13 and has been implicated in adipocyte differentiation. This gene now is known to be involved in the translocation breakpoint by fusing with FUS, another gene on chromosome 16 that has significant homology to the EWS gene on chromosome 22.161,163 The resultant aberrant transcript may alter molecular pathways in adipocyte differentiation in a way that contributes to the development of myxoid liposarcomas. Benign soft-tissue tumors such as lipomas, leiomyomata, and pleomorphic adenoma of the salivary gland with cytogenetically detectable abnormalities in the 12q13-15 region, do not demonstrate rearrangement of the CHOP gene. This indicates that a different breakpoint and other genes are involved in these benign tumors.

Of particular interest now are specific translocations that have been observed in distinct soft-tissue sarcoma types.202 In leukemias and lymphomas, translocations have long been shown to be associated with the control of expression or rearrangements of particular genes. The t(2;13) associated with alveolar rhabdomyosarcomas and the t(12;16) in myeloid liposarcoma are additional recently cloned translocations. The gene on chromosome 2 that is involved in the t(2;13)(q35;q14), which occurs in approximately 50% of cases of alveolar rhabdomyosarcomas, has been identified as PAX3.206,207 The PAX genes are a highly conserved gene family that includes nine members. This translocation results in the formation of a chimeric transcript consisting of the 5' portion of PAX3, including an intact DNA-binding domain fused to the FKHR gene on chromosome 13. The t(1;13)(p36;q14) also seen in alveolar rhabdomyosarcomas results in the fusion of another member of the PAX family, PAX7 to the FKHR gene on chromosome 13.203–205 Although detection of the chimeric transcript is a useful diagnostic tool in evaluating these tumors, it remains to be determined how this novel gene-fusion product relates to the development of rhabdomyosarcoma. pax3 and pax7 are specifically expressed in the dorsal neural tube and the developing somites. Loss-of-function mutations of pax3 in Splotch mice and in Waardenburg syndrome in man revealed that pax3 is necessary for the proper formation of caudal neural crest derivatives and for the migration of myoblasts into the limb. Mice with a mutated pax7 gene suffer from defects in cephalic neural crest derivatives only and indicate that both genes may functionally share some redundancy. The analyses of pax3 and pax7 function in normal development indicate that pax3 (possibly also pax7) triggers neoplastic development by maintaining cells in a deregulated undifferentiated and proliferative state in alveolar rhabdomyosarcomas.202,205

The chromosomal abnormality in synovial sarcoma [t(X;18) (p11.2;q11.2)] also is of interest because it is the first one involving a sex chromosome. This abnormality does not appear to be restricted to a particular histologic pattern.206,207 The t(X;18)(p11.2;q11.2) results in the fusion of the chromosome 18 SYT gene to either of two distinct genes, SSX1 or SSX2, at Xp11.2. SSX1 and SSX2 genes encode closely related proteins (81% identity) of 188 amino acids that are rich in charged amino acids. The N-terminal portion of each SSX protein exhibits homology to the Kruppel-associated box (KRAB), a transcriptional repressor domain previously found only in Kruppel-type zinc finger proteins. PCR analysis demonstrates the presence of SYT-SSX1 or SYT-SSX2 fusion transcripts in 29 of 32 of the synovial sarcomas examined, indicating that the detection of these hybrid transcripts by PCR may represent a very useful diagnostic method.206,207

Neurogenic Tumors


There have been several reports of the cytogenetic abnormalities of these malignant brain tumors, covering all histologic subtypes of gliomas, including astrocytomas, oligodendroglioma, and glioblastoma multiforme. In 1971, Mark145 demonstrated that 37 of 50 gliomas had near-diploid stem lines and that 26% contained double minute chromosomes (dmin). This study was done before the availability of banding techniques; with banding techniques, many more gliomas have been studied. Jenkins and colleagues208 reported on 53 gliomas. No specific abnormalities were detected, but the most frequent findings were dmin, structural abnormalities of chromosome 9 [del(9p) or translocation], trisomy 7, and loss of chromosomes 10, 18, and 22.209,210 In a report by Bigner and colleagues,209 8 of 22 tumors contained marker chromosomes derived from chromosome 9; in 3 tumors, both chromosome 9 homologues participated in marker formation with different breakpoints for a total of 11 structural rearrangements of this chromosome. In this series, the most prevalent finding was abnormalities of chromosome 9 with breakpoints at the centromere or in 9p. A candidate tumor-suppressor gene CDKN2 (p16INK4) recently was identified from 9p21.211 This gene is deleted in 70% of glioma cell lines and primary glioma tissues.212–214 Mutations of p53, deletions of 9p and of the CKDN2 gene, loss of chromosome 10, and EGFR amplification are critical genetic events in glioma progression.214 The tumor suppressor gene on 10q was recently identified as PTEN/MMAC1, a gene that encodes a protein that contains sequence motifs with significant homology to the catalytic domain of protein phosphatases and to the cytoskeletal proteins, tensin and auxilin. PTEN, appears to be mutated at considerable frequency in human cancers including in glioblastoma cell lines and xenografts, prostate cancer cell lines, breast cancer cell lines and xenografts, and primary glioblastomas.215,216

Ewing’s Sarcoma

Aurias and colleagues217 as well as Turc-Carel and colleagues218 independently described a t(11;22)(q24;q12) in the malignant cells of patients with Ewing’s sarcoma. This translocation has now been detected in more than 90% of these tumors, and the genes involved in this translocation have been cloned. The translocation involves the fusion of the human FLI1 gene on chromosome 11, with coding sequence of the EWS gene in chromosome 22 resulting in a fusion protein.165 The same chromosomal translocation has been described for peripheral neuroepithelioma and Ewing’s sarcoma.


In 1984, Whang-Peng and colleagues219 described a t(11;22)(q24;q12) in two cases of peripheral neuroepithelioma, which is the same translocation reported in more than 90% of Ewing’s sarcoma tumors.217,218 Furthermore, a comparison of Ewing’s sarcoma and neuroepithelioma suggests that these two tumors are histogenetically related, and it recently was shown that the neuronal phenotype of Ewing’s sarcoma and neuroepithelioma is the same. In both Ewing’s sarcoma and neuroepithelioma (i.e., two round-cell tumors of childhood), there is an association with a reciprocal t(11;22)(q24;q12). The discovery of the same identical translocation in neuroepithelioma and Ewing’s sarcoma has changed the treatment modality in neuroepithelioma.220 Use of therapy similar to that for Ewing’s sarcoma has resulted in a marked improvement in the response of these tumors. The current thinking is that Ewing’s sarcoma arises from cells of the neural crest.

Embryonic Tumors

Embryonic tumors are of particular interest to the cytogeneticist because some occur in patients with specific constitutional chromosomal abnormalities. In all preceding sections, the karyotypic changes have been somatic mutations in malignant cells, and they have not been present in other unaffected cells except in the few cases of familial renal cell carcinoma. In contrast, some patients who are at risk of developing retinoblastoma have a variable deletion of chromosome 13 that always includes 13q14, whereas other patients with a deletion of chromosome 11 (band 11p13) are at risk of developing Wilms’ tumor. In general, these sporadic deletions also are associated with various phenotypic abnormalities.1 Furthermore, analysis of tumor cells from patients with normal constitutional karyotypes indicates that approximately 5% of cases have tumor-specific deletions of chromosome 13, each of which includes deletions of chromosome 13, band q14. Relatively few tumors have been analyzed, however, and monosomy 13 or del(13q) are observed in less than 20% of tumor cells from some patients with retinoblastoma. These deletion cases were useful in defining the region of the genome likely to contain a locus involved in the genesis of retinoblastoma.2 Further analysis of this locus using methods of molecular cloning led to the identification of the RB1 gene.221–223 Suppression of tumorigenicity of human prostate carcinoma cells by replacing a mutated RB gene has been demonstrated, and the RB protein serves as an important regulatory function in controlling the cell cycle.224 The most common change that we have observed in Wilms’ tumors is trisomy for the long arm of chromosome 1 (11q), whereas deletions of 11p13 or unbalanced translocations occur in approximately 25% of cases.225 Recent studies suggest that three genetic loci are implicated in the development of Wilms’ tumor. One locus, which is associated with the WAGR (Wilms’ tumor, aniridia, genitourinary dysplasia, and mental retardation) syndrome, maps to 11p13226–229; another locus, which is associated with the Beckwith-Wiedemann syndrome, maps to 11p15; the third locus, which may be involved in familial predisposition to Wilms’ tumor, was not genetically linked to any of the markers on 11p and may be on another chromosome.229 Two groups have independently isolated a candidate gene (WT1) for Wilms’ tumor at 11p13, and the characterization of mutations in tumor DNA suggests that the gene product contributes to the malignant process.230,231

Recurring chromosomal abnormalities limited to the malignant cells, also have been observed in other childhood tumors; for example, a deletion of much of the short arm of chromosome 1 [del(1p)] has been noted in neuroblastomas.232 In addition, neuroblastomas are of interest because of their proclivity to undergo gene amplification, which manifests chromosomally as hundreds or thousands of small, discrete pieces of chromosomes called double minutes or long unbanded regions on chromosomes called homogeneously staining regions or HSR.232 In some cell lines, these have been shown to represent amplification of MYCN. MYCN amplification also has been identified in tumor samples, and it is highly correlated with advanced stage (i.e., III and IV) and with a poor survival of these patients.233,234

Germ Cell Tumors

Atkin and Baker235 described an isochromosome for the short arm of chromosome 12 in four seminomas in 1983 [i(12p)]. The presence of this marker in various histologic types of germ cell tumors, including seminomas, teratomas, and embryonal cell carcinomas, has subsequently been confirmed in several studies.1,235 Thus, i(12p) appears to be a highly consistent and specific cytogenetic abnormality associated with testicular germ cell tumors. Moreover, an increasing number of copies of 12p appears to be correlated with more aggressive disease and poorer survival.

Malignant Melanoma

Changes involving chromosomes 1, 6, and 7 have often been reported in the malignant cells of patients with melanoma.236 Most tumors studied have been metastatic, and there are few studies of early melanocytic lesions. Recent data from Parmiter and colleagues confirm that the predominant, nonrandom abnormality in metastatic melanoma continues to be deletions and rearrangements of 1p, abnormalities of 6p and 6q, extra copies of chromosome 7, and losses of chromosome 10.237,238 A translocation involving the terminal region 10q(q24-26) also was seen in some premalignant lesions, and the abnormalities of chromosome 10 were seen in both early and late lesions, suggesting that this may be a primary event in the malignant process.

Cowan and colleagues239 described loss of one copy of chromosome 9 in two of four dysplastic nevi and 4 of 11 melanomas. Isochromosome 1q [i(1q)] or del(1p) occur in approximately 60% of all tumors, whereas chromosome 6 is rearranged in more than 80% of all tumors.237 Trent and colleagues240 recently presented evidence that the insertion of a normal chromosome 6 could revert some of the malignant phenotype in malignant melanoma. CDKN2 (p16), a gene that is involved in the cell cycle, has been shown to be frequently deleted in melanoma cell lines.211 In addition, germline mutations of this gene were recently demonstrated in cases of 9p-linked familial melanoma.241 A consensus statement of the Melanoma Genetics Consortium was recently published. This statement outlines guidelines for counseling and DNA testing for individuals perceived to be genetically predisposed to melanoma.242

Molecular Analysis of Recurring Chromosome Abnormalities, Particularly Translocations

How and When Consistent Translocations Occur

We do not know how consistent structural rearrangements occur, but there are at least two possibilities. Rearrangements may be random, but selection may act to eliminate the vast majority that do not provide the cell with a proliferative advantage. Alternatively, certain changes may occur preferentially and, thus, may be the ones that we see. Some tantalizing data show an association of chromosome rearrangements in tumor cells from patients with fragile sites affecting one of the chromosome bands broken in the tumor cells.The cloning of the FHIT gene at the fragile site 3p14 has raised many questions about the relationship of this gene to fragile sites and malignancy.243 Much more research is required, however, to clarify the role of fragile sites as a predisposing factor to malignant transformation.

Croce and colleagues135 and Rabbitts87 have proposed that many of the chromosome rearrangements in B- and T-cell tumors involve sequences used in the normal recombination of the V-D-J segments of the immunoglobulin and T-cell receptor genes. The presence of heptamer and nonamer sequences in the nonimmunoglobulin gene at the site of the translocation, namely, MYC and BCL2, has been reported. However, there is no indication at present that the genes involved in the translocations in myeloid leukemias undergo similar DNA rearrangements. In fact, ALU sequences have been identified at some breakpoints.244,245 The role of topoisomerase II (topo II) cleavage sites has been studied because of the association of topo II inhibitors such as the epipodophyllotoxins and anthracyclines in treatment related AML. For example, the MLL gene has a single topo II cleavage site that colocalizes with some of the translocation breakpoints in t-AML.244,246

An equally important question is when in the multistage process of malignant transformation of a particular cell do translocations or other chromosomal aberrations occur? Some changes occur as part of the further evolution of the malignant phenotype (e.g., blast crisis of CML); therefore, they are relatively late events. However, what about the occurrence of the t(9;22) in CML, for example? Does the Ph chromosome occur in a single normal cell, which becomes the progenitor of the leukemic clone, or is there expansion of a clone, possibly a leukemic one, in which a translocation occurs in one of these already abnormal cells? Fialkow and colleagues247 have presented detailed evidence supporting the latter proposal.

Adams and colleagues108 have produced transgenic mice, all of whose cells have a vector containing the myc/IgH junction from a murine plasmacytoma. All cells contain this construct; however, the B-cell tumors that occur in every animal are clonal, indicating that one or more additional changes occur in one cell, resulting in clonality.

More recently, a number of investigators using RT-PCR have reported on the presence of a few cells with recurring translocations in normal individuals. For example, Schnittger and colleagues have detected partial tandem duplications of the MLL gene in peripheral blood and in bone marrow samples of healthy volunteers analysed by RT-PCR.248 This genetic alteration had previously been described as a novel finding in AML patients with normal karyotypes or with trisomy 11 as a sole chromosomal abnormality.245 Furthermore, studies of fetal spleens and cord blood from normal newborns revealed cells with the t(4;11).249 The detection of other translocations such as t(14;18), t(9;22) and t(8;21) have also been reported. Earlier, cytogenetecists described finding t(7;14), t(14;14) and inv(14) cells in PHA stimulated peripheral blood cultures of normal individuals at a frequency of about 1 in 5000 cells.

Thus, it appears that translocations occur at some relatively low frequency in some normal individuals. The children have not been followed long enough to determine whether the translocations will have any serious consequences. However, the presumption is that unless these cells sustain additional mutations, they will not lead to malignancy.

Biologic Consequences of Consistent Chromosome Abnormalities

The cloning of many chromosome translocation breakpoints and identification of the involved genes have had a major impact on our understanding of at least one critical event in the transformation of a normal cell to a leukemic cell.87 Translocations in the lymphoid leukemias and lymphomas that involve the immunoglobulin genes in B-lineage tumors and the T-cell receptor genes in T-lineage tumors result in inappropriate expression of the other gene in the translocation but no alteration in its protein structure. In contrast, all of the translocations cloned to date in the myeloid leukemias (with one possible exception) result in a fusion mRNA and a chimeric protein. This same situation is true for the 1;19 translocation in pre-B ALL and the 4;11 and 11;19 translocations in ALL, and all of the translocations in the mesodermal tumors.5,87 Cloning of the translocation breakpoints has led to the identification of a number of new genes (Table 6.6). It has been pointed out repeatedly that genes cloned from the breakpoints in acute leukemia have been transcription factors. In fact, one could argue that cloning these junctions is a very effective method for identifying new transcription factors.

Table 6.6. Functional Classification of Transforming Genes at Translocation Junctions.

Table 6.6

Functional Classification of Transforming Genes at Translocation Junctions.

Our new sophistication regarding genetic changes in hematologic malignant disease provides us with some very critical new diagnostic tools. Standard Southern blot analysis of tumor DNA can reveal clonal rearrangements of genes using the appropriate probes. PCR can increase the sensitivity of detection of these aberrations and multiplex PCR can improve efficiency of this detection. The sensitivity is sometimes too great to be clinically applicable. The future use of cDNA (complementary DNA) microarrays will certainly dramatically transform our ability to do genetic screening for translocations as well as mutations.250 Currently, there are over 1,000,000 human expressed sequence tag (EST) sequences available on the public database representing perhaps 50 to 90% of all human genes. The cDNA microarray technique exploits this wealth of information for the analysis of gene expression. DNA probes representing cDNA clones are arrayed onto a glass slide and interrogated with fluorescently labelled cDNA targets. The power of the technology is the ability to perform a genome-wide expression profile of thousands of genes in one experiment.251

Our increasing precision in identifying the genetic changes in malignant cells comes at a most opportune time, because physicians are now in a position to use targeted therapy aimed at the specific genetic defect in the malignant cells as has been done with BCR-ABL protein through the use of a specific abelson kinase inhibitor. To use this targeted therapy effectively requires a precise genotype of the malignant cells. Although a number of genes will be involved in various genetic alterations leading to a tumor cell, those reflected in chromosomal changes may be among the easiest to monitor.

Table 6.5A. Recurring Structural Abnormalities in Benign Solid Tumors.

Table 6.5A

Recurring Structural Abnormalities in Benign Solid Tumors.

Table 6.5B. Recurring Structural Abnormalities in Malignant Solid Tumors.

Table 6.5B

Recurring Structural Abnormalities in Malignant Solid Tumors.


Supported by grants CA 42557 to JDR and CA 68341 tro 010.


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