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Key Points

  • Disease summary:

    • Familial cancer syndromes are defined as cancers that arise in families with a genetic predisposition to develop cancer.

    • To date, up to 10% of all cancer diagnoses are in individuals with an inherited genetic mutation causing increased risk. Most of the common syndromes are a result of autosomal dominant mutations and result in earlier age at cancer diagnosis than those found in the general population.

    • Familial cancer predisposition may refer to syndromes where one or two types of cancer are dominant, such as breast and ovarian cancer in BRCA1 mutation carriers. Alternatively, familial cancer syndromes may refer to syndromes which result in multiple affected organs, such as the case with HNPCC (Lynch syndrome) whereby mutations in DNA mismatch repair genes confer an increased risk to multiple types of cancers, for example, large and small bowel, uterus, stomach, ovaries, urinary tract, etc.

    • As the ability to identify and understand the genetic and genomic changes in an individual progresses, our understanding of inherited risk is likely to change. Models which incorporate multifactorial genetic and environmental influences will evolve to better assess familial risk.

  • Differential diagnosis:

    • The differential diagnosis includes sporadic cancers and environmental or carcinogen risk-associated cancers. The differential must include careful consideration of a patient’s family history and consideration of identifiable risk factors (such as tobacco use, asbestos exposure, etc). A careful assessment of familial and environmental risk factors is essential to determining whether to pursue genetic testing.

  • Monogenic forms:

    • Several examples of a single gene causing cancer are known. The most common examples include but are not limited to p53 (Li-Fraumeni syndrome), BRCA1 or BRCA2 (breast or ovarian syndromes), mismatch repair genes (Lynch syndrome), and the APC gene (familial adenomatous polyposis [FAP]).

  • Family history:

    • Taking a detailed family history is critical for identifying a familial cancer syndrome. This includes obtaining information on first-, second-, and third-degree relatives. For many of the cancer syndromes, there are established diagnostic criteria for determining whether a family may harbor a predisposing gene.

  • Twin studies:

    • To date, twin studies are limited by the challenge of differentiating common environmental factors from heritable risk. However, twin studies do suggest an increased risk among twins when one twin is affected. This is particularly true for colorectal, lung, breast, prostate, and stomach cancer and if the affected individual is young at the time of cancer diagnosis.

  • Environmental factors:

    • There are numerous environmental factors (carcinogens) which are associated with an increased cancer risk. Carcinogens are identified as any substance (including radiation) with the capacity to perturb the cellular metabolic functions or genome directly. Furthermore, heritable risk is not independent of environmental risk. The environment can uniquely affect predisposing heritable risks, by tipping the balance toward the development of cancer in those patients with underlying risk factors.

  • Genome wide associations with common variants:

    • With respect to cancer heritability, numerous ...

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