Specific syndromes

Oxford American handbook of oncology. Second Edition. Oxford University Press (2015)


Over 50 cancer predisposition syndromes have been identified, with a variety of classification systems proposed.

  • These systems are based on features such as the organ(s) predominantly affected with cancer, or the molecular role of the gene mutated.
  • No one system is uniformly accepted.

The following are noteworthy syndromes in adult oncology, listed by genes mutated in the syndrome with common name in parentheses; additional information is available in specific cancer chapters.

Hereditary “breast” syndromes

BRCA1/2 (breast/ovarian syndrome)

  • Approximately 5%–10% of breast cancer cases (approximately 18,000/year); population carrier estimates are approximately 1 in 500 to 1000.
  • 10% of ovarian cancer cases (approximately 2000/year).
  • BRCA1 penetrance is generally higher: breast risk to age 70 up to 70%; ovarian risk up to 40%. Breast cancers tend to happen at a younger age and are usually “triple-negative” in type.
  • BRCA2 penetrance is lower, with lifetime risks of breast cancer up to 50% and ovarian cancer up to 20%.
  • BRCA2 cancer risks also increased for pancreas, prostate, and melanoma; other cancer risks are less clear for BRCA1.
  • Male carriers for mutations in both genes are at increased risk for breast cancer, although higher with BRCA2.
  • Determination of mutation status in patients with breast cancer can guide local management and provide clear indication for oophorectomy as part of treatment.

P53 (Li-Fraumeni syndrome)

  • Increased risk for breast, soft tissue sarcoma, osteosarcoma, leukemia, brain tumors, and adrenocortical tumors in classic syndrome.
  • More recent studies suggest some increase in most adult epithelial cancers.
  • Population carrier estimates are approximately . in 5000, making it rare.

PTEN (Cowden’s syndrome)

  • Benign and malignant tumors of the breast, thyroid (follicular more than papillary; not medullary), and endometrium
  • Characteristic skin findings with lipomas, fibromas, and trichilemmomas

Checkpoint kinase 2 gene

  • Mutations in the checkpoint kinase 2 gene (CHEK2) likely function as a low penetrance gene for breast cancer and may confer a two- to three-fold increased risk of breast cancer compared to the general population, particularly in white women of European ancestry.
  • The clinical utility of testing for CHEK2 mutation is unclear but may be considered for white women with breast cancer who have a family history of breast cancer and no evidence of a mutation in the BRCA1/2 genes.

Serine threonine kinase (Peutz-Jeghers syndrome)

  • Mutations in the serine threonine kinase gene (STK11) associated with characteristic hamartomatous polyps in the gastrointestinal tract as well as mucocutaneous melanin pigmentations in the lips and buccal mucosa.
  • Autosomal dominant inheritance pattern associated with multiple cancers including those of the gastrointestinal system as well as cancers of the breast, ovary, uterus, and lung.
  • Cumulative risks of breast cancer and ovarian cancer are estimated at 55% and 20%, respectively.
  • Individuals with STK11 mutation or familial characteristics of Peutz-Jeghers syndrome should undergo regular screening of the gastrointestinal system for polyp detection (including upper endoscopy, video capsule endoscopy, and colonoscopy) as well as enhanced screening for other associated cancers (including annual breast MRI).
  • CDH1 (hereditary diffuse gastric cancer syndrome)
  • Autosomal dominant inheritance pattern. Mutations in the cadherin-1 gene (CDH.) are highly penetrant and associated with a lifetime risk of gastric cancer that exceeds 80%. These mutations are also strongly associated with increased lifetime risk, approximately 60%, of lobular breast cancer.
  • Carriers of CDH1 gene mutations may be counseled to consider prophylactic gastrectomy as well as enhanced screening for breast cancer (including annual breast MRI).

Hereditary gastrointestinal syndromes

Mismatch repair genes MLH1, MSH2, MSH6, PMS2 (Lynch syndrome or hereditary non-polyposis colon cancer)

  • Approximately 5% of colon cancer cases (5000 cases/year)
  • Predominance of right-sided colon cancers
  • Colon cancers have “mutator” phenotype, microsatellite instability, and better prognosis
  • Increased risk of endometrial, gastric, biliary tract, urinary tract, and ovarian cancers
  • Mutations also account for other eponymous syndromes: Turcot’s (glioblastomas plus colon cancer variant) and Muir-Torre (colon cancer plus sebaceous gland tumors)
  • Observational studies have demonstrated survival benefit to more intensive colon cancer screening when mutation carriers are identified

APC and MYH (polyposis syndromes)

  • Classic familial adenomatous polyposis (FAP) is usually clinically evident with the presence of thousands of colon polyps.
  • Virtually all patients with classic FAP develop colon cancer eventually if the colon is left in place.
  • Classic FAP is also associated with adenomas and carcinomas of the duodenum and rectum, desmoid tumors, osteomas, thyroid carcinoma, and hepatoblastomas (particularly in children).
  • Some APC mutations give an attenuated clinical picture with many fewer polyps, but they still markedly increased risk of cancer.
  • MYH-associated polyposis is a recessive disorder causing formation of fewer than 100 colon polyps, and associated colon cancer risk requiring more frequent screening.
  • MYH carrier prevalence is approximately 2% of the population.
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