Cancers arise from accumulated genetic and epigenetic alterations that dysregulate cellular pathways and processes. Some patients with cancer harbor germline sequence variants that increase their cancer risk relative to the general population, but the particular mutant allele, other cellular genes, and varied life exposures collectively contribute to the lifetime cancer risk of 1 or more cancers in each patient. The contribution of germline mutations varies by gene and tumor type. About 25% of patients with medullary thyroid cancer (MTC) carry germline-activating mutations in the RET gene that underlie multiple endocrine neoplasia type 2 or familial MTC. The high prevalence of RET germline mutations in patients with MTC coupled with the high likelihood that cancer will arise in a RET mutation carrier justifies the recommendation that all patients with MTC undergo genetic testing. In contrast, germline heterozygous mutations in the ATM (ataxia telangiectasia mutated) tumor suppressor gene are present in about 1% of the general population, and heterozygous ATM mutations increase breast cancer risk by about 2- to 3-fold,1 highlighting why screening for ATM mutations in patients with breast cancer is not recommended.
Stoffel EM, Fearon ER. Germline Sequence Variants and Ovarian Cancer: Known-Knowns and Known-Unknowns. JAMA Oncol. 2016;2(4):491–492. doi:10.1001/jamaoncol.2015.5622
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