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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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Cancer-Associated Genodermatoses

, MD, PhD, , MD, , MD, and , MD.


Ataxia-telangiectasia (AT) is inherited as an autosomal recessive disorder. The frequency of gene mutations in the general population is approximately 1.4%,216 and disease incidence is 1 in 30,000 to 1 in 100,000. Cerebellar ataxia is present in all patients, becoming evident as the child learns to walk. The ataxia is truncal at first, but gradually comes to include ataxia of gait, intention tremor, dystonia, slurred speech, and apraxia of eye movements. Oculocutaneous telangiectasia begins in late childhood. Other cutaneous signs are vitiligo, café-au-lait spots, and premature graying of the hair. Cellular and humoral immune deficiency is common, probably accounting for frequent sinopulmonary infections. Endocrine dysfunction (glucose intolerance, hypogonadism) is seen in half of affected individuals. AT patients are unusually sensitive to ionizing radiation, and conventional radiation therapy regimens can be fatal.

The AT gene is located on chromosome 11q22–23217, 218 and is designated ATM.219 AT variants (Nijmegen breakage syndrome and Berlin breakage syndrome) are both linked to 8q21, indicating that they are not allelic with AT. Most reported AT mutations result in truncated protein. There are several hundred mutations, with very few spontaneously recurring ATM mutations, making population screening difficult.220 Radio-resistant DNA synthesis is the best diagnostic test for AT. The test is available from a few reference laboratories.

Approximately 15% of AT patients will die of cancer, with non-Hodgkin lymphoma, leukemia, and gastric cancer predominating. Medulloblastoma and glioma have also been described in AT patients. McConville and colleagues221 describe 14 families with ATM mutations and a less-severe phenotype and suggest that cancer predisposition may be variable among families. This heterogeneity could result from the position of the ATM mutation or the type of mutation involved (eg, missense vs large deletion).

Heterozygotes are at increased risk for breast cancer. Swift and colleagues222 reported a 6.8-fold increased risk in such patients. Athma and colleagues216 found increased risk for breast cancer in both younger women (2.9 relative risk) and in women older than age 60 years (6.4 relative risk). The authors estimate that 6.6% of breast cancers in the United States occur in women who are AT heterozygotes.

We believe that heterozygous women should begin breast cancer screening at age 30 years, with regular self-examination and yearly mammograms.

Bloom Syndrome

Bloom syndrome (BS) is a rare (approximately 170 known cases), autosomal recessive disease that occurs more frequently among Ashkenazi Jews than in other groups. The BLM gene is on chromosome 15q26.1. Multiple mutations are possible; the predominant mutation is referred to as “blm,” which is a 6-bp deletion, and 7-bp insertion at nucleotide position 2281 in the BLM cDNA.223 Founder mutations have been described in Ashkenazi Jews.223 BS somatic cells are hypermutable, with markedly elevated chromosome breakage and sister chromatid exchange.

Affected individuals present with short stature, sun-sensitive facial erythema, malar hypoplasia, nasal prominence, small mandible, and dolichocephalic skull.224 There is immunodeficiency, manifested by bronchitis and bronchiectasis. The hypermutable DNA is responsible for increased frequency of malignancy, with leukemia and lymphoma predominating in younger patients and carcinomas of larynx, lung, esophagus, colon, breast, and cervix seen in adults. The carcinomas arise about 20 years earlier than expected for the general population.225

Gruber and colleagues226 found that Ashkenazi Jews with CRC were more than twice as likely to be heterozygous for the BLM mutation than Ashkenazi Jewish controls without CRC (odds ratio [OR] = 2.45; 95% confidence interval [CI] 1.3 to 4.8; p = 0.0065). In contrast, the Israeli Ashkenazi Jewish population controls showed an absence of BLM carriers, thereby decreasing the likelihood that the results could be biased. Their data were supported by findings in a recent mouse model227 of Bloom syndrome, which tested the effect of Blm haploinsufficiency and the risk of cancer in mutation carriers. Mice that were heterozygous for Blm developed twice the number of intestinal tumors when crossed with mice carrying a mutation of the Apc tumor-suppressor gene.227 Gruber and colleagues concluded that, “…Our data similarly show that carriers of a BLM mutation have an increased risk for CRC. Possible mechanisms of carcinogenesis include (i) haploinsufficiency, in which a half dose of BLM gene product is insufficient for full BLM function in the maintenance of genomic integrity, giving rise to an increased mutation rate in the heterozygous cell, and (ii) loss of the normal BLM allele in a colonic stem cell, giving rise to a cell clone with the same hypermutability as the Bloom syndrome cell. Whichever the mechanism, our data confirm the importance of genomic instability as a critical element in the pathogenesis of cancer.”226

Cowden Syndrome and the Multiple Hamartoma Syndromes

Cowden syndrome (CS) is an autosomal, dominantly inherited, rare disorder that was the first of the multiple hamartoma syndromes to lend itself to genetic characterization. This syndrome has shared overlapping presentations with BRR and JPS. Of greatest interest to the practicing oncologist is the fact that CS patients carry a 25% to 50% lifetime risk of breast cancer and a 3% to 10% lifetime risk of thyroid cancer (for review see Eng228). Unlike CS, BRR does not carry an increased risk of cancer but is now known to be caused by mutations in the same gene, PTEN.229, 230

CS is associated with multiple hamartoma, including gastrointestinal hamartomatous polyps and benign and malignant neoplasms of the breast, thyroid, uterus, and skin. It is also associated with facial trichilemmomas, acral keratosis, and verrucoid or papillomatous papules in virtually all cases. CS is associated with CNS defects in 40% of cases.228 Cerebellar dysplastic gangliocytoma, also known as Lhermitte-Duclos disease (LDD), is now established as part of the clinical spectrum of CS.231 Although 90% of CS patients demonstrate symptoms by the age of 20 years, only 10% exhibit symptoms prior to age 10 years.232

In 1996, CS was mapped to the locus 10q22-23,232 a region frequently deleted in thyroid tumors.233 Somatic mutations spanning this region were also commonly found in glioblastoma, breast cancers (in association with CS), and advanced prostate cancer.234 In 1997, PTEN was isolated and identified as the gene responsible for CS. PTEN consists of 9 exons spanning 100 kb of DNA.229, 234–236 PTEN is a major lipid 3-phosphatase, which signals down the PI3 kinase/AKT pro-apoptotic pathway. Furthermore, PTEN is a protein phosphatase, with the ability to dephosphorylate both serine and threonine residues. The protein-phosphatase activity has also been shown to regulate cell-survival pathways, such as the mitogen-activated kinase (MAPK) pathway. Although it is well established that PTEN's lipid-phosphatase activity, via the PI3K/AKT pathway, mediates growth suppression, there is accumulating evidence that the protein-phosphatase/MAPK pathway is equally important in the mediation of growth arrest and other crucial cellular functions.237 All genetic and biochemical studies indicate that PTEN acts as a classic tumor-suppressor gene.

In 1996, the International Cowden Syndrome Consortium created a set of major and minor criteria to aid in the diagnosis of Cowden syndrome. Of the 37 CS families and 7 BRR families identified by using these criteria, 81% had a PTEN mutation.238 Mutations were scattered throughout the gene, but a mutation “hotspot” in exon 5 accounted for 43% of the mutations found in the region encoding the protein tyrosine phosphatase. When mutations in exons 7 and 8, which encode potential phosphorylation sites, were included, the mutation rate increased to 77%.239

PTEN screening of BRR families revealed that approximately 50% had mutations for this gene.238 However, only 10% of JPS patients were PTEN mutation carriers, and many of those already showed signs of CS or subsequently developed them. Thus JPS is thought to be a variant of CS with incomplete expressivity.98 The clinical significance of this association is that patients with JPS and a mutation in PTEN may benefit from enhanced screening of the breast, thyroid, skin, and uterus. Finally, when patients with symptoms suggestive of CS but not fulfilling the CS criteria (“CS-like syndromes”) were screened for mutations in PTEN, only 1 in 64 (2%) of patients carried mutations,239 supporting the strict use of the International Cowden Consortium criteria for CS.

Attempts to correlate the PTEN genotype and phenotype have been limited by small sample size. PTEN mutations are associated with LDD in some families,229, 240 but are not clustered in a specific region of the gene. A trend for greater organ site involvement (5 vs 4 or fewer sites) is associated with mutations in the protein tyrosine phosphorylase core region; however, larger sample sizes are needed to verify these results.238 A screen of 177 breast cancer patients with a family history of breast cancer but negative for BRCA1 and BRCA2 failed to show PTEN coding mutations.241 Therefore, there appears to be no increased risk of breast cancer in the absence of the other manifestations of CS, and the screening of these patients for PTEN is unwarranted.

Identification of a PTEN mutation in a patient is diagnostic for either CS or BRR, but a negative mutation screen is nondiagnostic.98 PTEN carriers should be screened for thyroid and breast cancers starting in their twenties or 5 years earlier than the youngest relative who developed disease. Future work will likely focus on the variable phenotype of PTEN mutations. These studies may reveal less penetrant genes that modify the phenotypic expression of PTEN mutations.

Fanconi Anemia

Fanconi anemia (FA) is inherited as an autosomal recessive disorder. There are five complementation groups: FA-A at 16q24.3; FA-B (unmapped); FA-C at 9q22.3; FA-D at 3p26-p22; and FA-E (unmapped). The carrier frequency is higher in Ashkenazi Jews (1 in 100), and a founder mutation of FA-C has been described in that population.242 The cells of homozygotes have chromosomal instability that can be demonstrated as enhancement of chromosome breakage in a mitomycin C chromosome stress test.243

Progressive pancytopenia is the principal feature of FA, presenting as anemia, bleeding, and easy bruising in children. Multiple congenital abnormalities are seen in roughly two-thirds of FA patients; these include hyperpigmentation of the skin, café-au-lait spots, skeletal deformities, renal malformations, microphthalmia, ear anomalies and deafness, congenital heart disease, and hypogonadism.

FA patients are at risk for myelodysplastic syndromes and leukemia, usually acute myelogenous leukemia. Hepatocellular carcinoma has been described in approximately 5% of patients, possibly secondary to anabolic steroid therapy for anemia. Squamous carcinomas of the upper aerodigestive tract, cervix, vulva, and anus can also complicate the course of FA. The FA-A locus on 16q24.3 is an area that often shows loss of heterozygosity in breast cancer. Cleton-Jansen and colleagues244 have shown that the FA-A gene is not the culprit gene in breast cancer, concluding that “another tumour suppressor gene in this chromosomal region remains to be identified.”

Werner Syndrome

Werner syndrome (WS) is inherited as autosomal recessive. The incidence is estimated at 1 in 50,000 to 1 in 100,000. Its phenotype is characterized by premature aging, with growth arrest at puberty, cataracts occurring in the second and third decades, premature atherosclerosis, and adult-onset diabetes. The average life span is 47 years.

The WS locus, WRN, maps to chromosomal region 8p12.245–250 The gene encodes a DNA helicase of 1,432 amino acid residues. Bennett and colleagues245 note that the helicase consensus domain region of WRN has sequence homology with the bacterial RecQ family of helicases, including BLM, the BS gene product.251 Bennett and colleagues245 identified MMR in fibroblastoid cells but not in lymphoblastoid cells, a finding that is consistent “…with the possibility that WRN protein could have a cell type- and/or tissue-specific role in mismatch repair. Alternatively, a mutation in WRN could predispose cells to mutations in other genes required for mismatch repair activity, at least one of which could be an unknown gene.”245

Malignant neoplasms associated with WS include sarcoma, melanoma, and carcinoma.252 The sarcoma:melanoma ratio in WS is 1:1, in contrast to the 10:1 ratio in the general population. Organs at risk for carcinoma include the thyroid, stomach, liver, breast, and bile duct. Melanomas may arise in unusual locations, such as the nasal cavity.

Risks and benefits of cancer screening in this syndrome have not been established, but regular melanoma surveillance seems reasonable.

Xeroderma Pigmentosum

Xeroderma pigmentosum (XP), mentioned earlier, is inherited as autosomal recessive. The incidence is 1 in 1,000,000 in the United States but 1 in 40,000 in Japan. XP is genetically heterogeneous, with causative loci mapped to 9q34.1 (XP-A); 2q21 (XP-B); 3p25.1 (XP-C); 19q13.2 (XP-D); 11p12-p11 (XP-E); 16p13.2-p13.1 (XP-F); and 13q32–q33 (XP-G). All of the culprit genes play roles in excision repair of DNA pyrimidine dimers induced by ultraviolet light. Mutation analysis is not available as a clinical test.

Affected individuals show an extraordinary hypersensitivity to sun exposure, manifested by childhood onset of photosensitivity, freckling, and irregular pigmentation. Kraemer and colleagues253 indicate that the frequencies for malignant melanoma and epithelial cancers (squamous and basal cell carcinoma) are respectively 2,000- and 4,800-fold higher in XP patients than their occurrence in the general population of the United States. The median age of the initial cancer in XP is about 8 years, which is close to 50 years earlier than its occurrence in the general population of the United States. Lanza and colleagues254 note that XP lacks the marked spontaneous chromosomal instability that characterizes other hereditary disorders that show hypersensitivity to mutations with the predisposition to neoplasia, inclusive of AT, FA, and BS. Cellular hypersensitivity to ultraviolet radiation is the hallmark of XP. Laboratory testing for XP is available from reference laboratories.

XP patients are at increased risk for noncutaneous malignancies as well. Brain tumors, leukemias, and carcinomas of lung and stomach have been described. Cultured cells from XP patients are hypersensitive to DNA-binding carcinogens in cigarette smoke and charbroiled food. Neurologic abnormalities are described in 20% of XP patients, and genetic evidence suggests overlap between XP and Cockayne syndrome (dwarfism with microcephaly, progressive neurologic degeneration, and photosensitivity).255

Affected individuals must avoid exposure to carcinogenic effects of sunlight.256 Assiduous protection from sunlight must begin in infancy, with wide-brimmed hats, long sleeves, and outdoor activities limited to after sunset. Regular examination of skin and eyes, with early excision of lesions, is mandatory. Avoidance of cigarette smoke and grilled food is probably advisable.257

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

Copyright © 2003, BC Decker Inc.
Bookshelf ID: NBK13680


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