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The genetics of inherited cancers 

The genetics of inherited cancers

The genetics of inherited cancers

Rosalind A. Eeles


July 30, 2015: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.

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date: 24 March 2017

All cancer can be termed ‘genetic’ as cancer is caused by somatic cell mutations (alterations in the DNA code), which result in abnormal cellular growth and/or proliferation. Most of these mutations are sporadic (only occurring in the cancer cell), but some are due to the inheritance of a germ-line mutation in a cancer predisposition gene.

Cancer predisposition genes can be rare and confer a high cancer risk (about 10-fold lifetime relative risk), or common and confer a moderately increased risk (from just over onefold, up to two- to threefold). They have been shown to be involved in causing some of most common cancers as well as some rare cancers.

Mechanisms of inherited cancers

Cancer predisposition genes (see Chapter 6.2) are usually (1) tumour suppressor genes—e.g. retinoblastoma caused by mutations in RB1—when, although the mutations are recessively inherited at the cellular level, they tend to manifest with a dominant inheritance pattern because the chance of a mutation being inherited by the offspring is 50%, and a sporadic mutation of the remaining normal allele occurs in a somatic cell during the lifetime of the germ-line mutation carrier to lead to cancer development; (2) oncogenes—e.g. the RET oncogene in the multiple endocrine neoplasia (MEN) type 2A syndrome—when gain-of-function mutations act in a dominant manner; (3) mismatch repair genes—e.g. causing the hereditary nonpolyposis colorectal cancer (HNPCC, Lynch) syndrome.

Clinical features

Genetic predisposition to cancer should be suspected when cancers: (1) occur at a younger age than is seen in the general population; (2) occur in more than one site or at multiple times at the same site in an individual (multiple primary tumours); or when (3) rare cancers are seen in clusters in a family; or (4) common cancers are seen in clusters in a family, often at young age or with multiple primaries.

Genetic predisposition to common cancers—this includes (1) breast—BRCA1 and BRCA2 mutations confer 80 to 85% risk of breast cancer by 80 years (and also a significantly increased risk of ovarian cancer); TP53 (Li–Fraumeni syndrome) mutations confer 90% risk of breast cancer by 60 years; (2) colon—mutations in the APC gene cause familial adenomatous polyposis (FAP) and a virtually 100% risk of colon cancer by the age of 40 years; HNPCC, which is also associated with other cancers in addition to colon cancer, particularly endometrial cancer (60% lifetime risk) and ovarian cancer (12% lifetime risk).

Rare inherited cancer syndromes—there are many of these, including hereditary retinoblastoma, neurofibromatosis type 1 (optic nerve glioma, sarcoma, phaeochromocytoma), neurofibromatosis type 2 (acoustic neuroma and other tumours of the central nervous system), MEN1 (parathyroid adenomas, pancreatic islet tumours and anterior pituitary tumours), MEN2A and 2B (medullary thyroid cancer, phaeochromocytoma, parathyroid adenomas), Cowden’s syndrome (breast and other cancers), tuberous sclerosis (childhood brain tumours, cardiac rhabdomyomas), Gorlin’s syndrome (multiple basal cell naevi/carcinomas), Von Hippel–Lindau syndrome (cerebellar and spinal hemangioblastomata, renal cell carcinoma, phaeochromocytoma, pancreatic tumours).

Clinical management

Patients and/or families known or suspected to carry cancer predisposition gene mutations require genetic counselling and risk assessment, which may lead on to (1) cancer screening—e.g. colonoscopy for some individuals at increased risk of colon cancer; (2) lifestyle changes—e.g. avoidance of known cancer-causing factors such as sunlight in Gorlin’s syndrome; (3) prevention strategies—e.g. prophylactic total colectomy in the FAP syndrome; (4) cancer treatment considerations—e.g. tumours with a particular genetic abnormality may respond to particular treatments; and (5) genetic testing—which may either be diagnostic (the detection of a mutation in an individual affected by cancer) or predictive (the detection of a mutation in a clinically unaffected individual).

Future prospects—gene alterations that predispose to cancer affect prognosis and treatment, hence genetic information is increasingly recognized as important in oncological practice. Cancer genetics will become part of mainstream clinical pathways for cancer care in the next decade and is likely to contribute to health care that is tailored to individual patients.

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