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Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003.

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Holland-Frei Cancer Medicine. 6th edition.

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DNA Repair Pathway Genes

, MD, PhD and , MD.

At the outset of the chapter, tumor-suppressor genes were defined as those genes inactivated by germ line or somatic mutations in cancer. It was also emphasized that DNA damagerecognition and repair genes constitute a subset of the tumor-suppressor gene class, because they are affected by inactivating mutations in cancer. Whereas tumor-suppressor genes such as RB1, p53, APC, and INK4a appear to have active roles in regulating cell growth and/or apoptosis, the DNA damage-recognition and repair genes can arguably be viewed as having more passive roles in processes controlling growth. Distinguishing between what constitutes a growth-regulating tumor-suppressor gene versus a DNA repair-type tumor-suppressor gene may be difficult because some tumor-suppressor genes, including perhaps p53, BRCA1, and BRCA2, may ultimately be established to have functions in both growth control and DNA repair. Nevertheless, based on present data, there is a reasonable basis to suggest that loss-of-function mutations in both alleles of certain DNA repair pathway genes, such as the DNA mismatch repair genes, probably do not directly alter cell growth. Rather, inactivation of DNA mismatch repair activity likely contributes to cancer via an increased frequency of mutations in other cellular genes, particularly genes that are rate determining in tumor development.

Several recessive cancer predisposition syndromes resulting from inactivation of genes that function in DNA damage recognition and repair have been well described, including ataxia-telangiectasia (AT), Bloom syndrome, xeroderma pigmentosum, and Fanconi anemia. In each case, the specific cancer types and DNA-damaging agents that increase cancer risk are essentially distinct. Although AT heterozygotes may have a subtly increased risk of breast cancer,264 in other recessive cancer syndromes, only homozygotes appear to have a clearly increased cancer risk. This observation contrasts sharply with the picture in the dominant cancer predisposition syndromes discussed earlier (eg, inherited retinoblastoma, familial adenomatous polyposis, NF1, and NF2), where heterozygotes have a clearly elevated cancer risk. Furthermore, as discussed earlier, the basis for increased cancer risk in an individual with a dominant cancer syndrome attributable to a germ line tumor-suppressor mutation (eg, RB1 or APC mutation) is that cancers arise following inactivation of the remaining normal copy of the gene by a second “hit” in somatic cells (ie, the Knudson hypothesis). Therefore, it seems reasonable to argue that second “hits” in tumor-suppressor genes of the type that underlie dominant cancer syndromes must have considerably more potent effects on initiating cancer development than second “hits” in tumor-suppressor genes of the type that underlie recessive cancer syndromes.

In light of these considerations and because recessive cancer syndromes are quite rare, our discussion of the role of DNA repair genes in cancer focuses on DNA mismatch repair gene mutations and HNPCC. The DNA mismatch repair (MMR) genes are also worthy of a more complete discussion because the genes appear to be inactivated in a considerable subset of sporadic cancers, including roughly 10 to 20% of colorectal, endometrial, and gastric cancers.

DNA Mismatch Repair Gene Defects and HNPCC

As for breast cancer, familial clustering of colon cancer has long been recognized, with perhaps 10 to 20% of all colon cancers attributable to the inheritance of a gene defect with a strong effect on cancer risk. Germ line APC mutations are responsible for 0.5 to 1% of colorectal cancer cases in the Western world, and HNPCC is responsible for approximately 2 to 4%.265–268 Diagnosis of HNPCC is problematic when only clinical criteria is used. First, overt clinical findings prior to cancer diagnosis, such as the florid intestinal polyposis seen in individuals with FAP, are lacking in individuals with HNPCC. Second, there is always a likelihood of chance clustering of cancer within a family for a common malignancy such as colorectal cancer. Nevertheless, diagnostic criteria for identifying those individuals and families most likely to be affected by HNPCC have been determined.265–268 Representative diagnostic criteria include (1) exclusion of familial polyposis; (2) colorectal cancer in at least three relatives, one of them being a first-degree relative of the others; (3) two or more successive generations affected; and (4) at least one of the affected individuals being younger than 50 years of age at the time of diagnosis. Even though not all individuals affected by HNPCC meet these criteria, the criteria are useful for excluding familial aggregations of colorectal cancer that are likely to have a genetic basis distinct from that underlying the majority of HNPCC cases.266, 267

Several genes responsible for HNPCC have been identified, including two on chromosome 2p (MSH2 and MSH6) and another on chromosome 3p (MLH1). Together, germ line mutations in the MSH2 and MLH1 genes account for virtually all classic HNPCC cases.266–270 The protein products of the MSH2 and MLH1 genes appear to have critical roles in the recognition and repair of DNA mismatches (Figure 7-10). A number of other gene-encoding proteins that function in mismatch repair have been identified, and mutations inactivating the PMS2 and MSH6 genes have been seen in a small fraction of those with HNPCC.266–271

Figure 7-10. Mismatch repair pathway in human cells.

Figure 7-10

Mismatch repair pathway in human cells. A and B, During DNA replication, DNA mismatches may arise, such as from strand slippage (shown) or misincorporation of bases (not shown). C, The mismatch is recognized by MutS homologs, perhaps most often MSH2 and (more...)

In cells with one normal and one mutant allele of a DNA mismatch repair gene, DNA repair is minimally impaired, if at all. However, inactivation of the remaining allele can occur as a result of somatic mutation in an initiated cell population during the earliest stages of tumor development. Once the cell acquires impaired mismatch repair function, for instance, as a result of inactivation of both alleles of either MSH2 or MLH1, hundreds of errors/mutations may arise and fail to be repaired during each cell-division cycle. Because these mutations preferentially arise in mononucleotide, dinucleotide, and trinucleotide repeat tracts (ie, microsatellite sequence tracts) the phenotype is often referred to as the microsatellite instability (MSI) phenotype.

Germ line mutations in the known MMR genes have only been detected in 2 to 4% of colorectal cancer patients, although approximately 10 to 15% of all colon cancers display the MSI phenotype.267–270, 272–274 It is clear that only a small fraction of the sporadic colorectal cancers with the MSI phenotype develop as the result of a germ line mutation in a known mismatch repair gene. Somatic mutations in mismatch repair genes have been found in some sporadic colorectal cancers with the MSI phenotype.275 In most sporadic cases, however, inactivation of the MLH1 gene occurs in association with methylation of its promoter.276, 277 The basis for the inactivation and the molecular mechanism(s) underlying the methylation are unknown.

Many of the mutations arising in cells with MMR deficiency are likely to be detrimental to cell growth or even lethal. A small fraction of the total mutations that arise presumably activate oncogenes or inactivate tumor-suppressor genes. Some genes are preferentially mutated in MMR-deficiency cancers, presumably because these mutations confer a selective growth advantage. For instance, genes that contain repetitive DNA sequences, such as microsatellite tracts, might be expected to be targets of mutation in these cancers and data support this prediction. An example of a gene containing a mononucleotide repeat tract in its coding sequence, and that is frequently inactivated in colorectal cancers with MMR-deficiency, is the type II receptor for transforming growth factor-β (TGF-β).

The TGF-β type II receptor is a compelling candidate tumor-suppressor gene, as both copies of the gene are inactivated by mutations in more than 90% of MSI colorectal cancers.278, 279 The TGF-β cytokine is known to inhibit the growth of many epithelial cells. Intriguingly, a recent study has suggested that germ line mutations in the cytoplasmic domain of the TGF-β type II receptor is associated with HNPCC,280 although it will be important to confirm this observation in additional HNPCC kindreds. Finally, a downstream effector of the TGF-β pathway, Smad4 (also called DPC4), was recently identified as a tumor-suppressor gene. SMAD4 is somatically mutated in 45 to 50% of pancreatic cancers, in 10 to 20% of colorectal cancers, and in a very small fraction of other cancers.281–283 Germ line inactivating mutations in SMAD4 are found in a major fraction of patients with juvenile polyposis syndrome (JPS).284 Those patients with JPS develop benign (hamartomatous, not adenomatous) polyps of the intestinal tract and are at increased risk of colorectal and gastric cancer.

Another recently suggested candidate for somatic inactivation in MMR-deficient colorectal cancers is the BAX gene,285 which is a potential p53-regulated gene encoding a Bcl-2-related pro-apoptotic protein. Finally, there are data suggesting that gain-of-function mutations in β-catenin arise preferentially in MSI colon cancers,164, 165, 286 although the β-catenin mutations are not present in a microsatellite tract. These mutation comparisons emphasize that it is the pathways rather than the specific genes that are best considered as targets of mutations. In MMR-proficient cancers, APC is much more frequently mutated than β-catenin, while the reverse is true for MMR-deficient cancers; these mutations have similar effects on the pathways through which APC and β-catenin control growth. Similarly, p53 is more often mutated than BAX and SMAD4 is more often mutated than TGF-β RII in MMR-proficient cancers, while the reverse is true for MMR-deficient cancers. This is one example of the ways in which the spectrum of somatic mutations in specific cancers can provide important clues to pathogenesis.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2003, BC Decker Inc.
Bookshelf ID: NBK12469

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