What is the role of genetics in the etiology of breast cancer?

Updated: Dec 26, 2019
  • Author: Graham A Colditz, MD, DrPH; Chief Editor: Chandandeep Nagi, MD  more...
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Family history of breast cancer in a first-degree relative is a consistent risk factor; risk increases with earlier age at diagnosis in the relatives and the number of relatives affected. In the Nurses' Health Study, for instance, the RR associated with a maternal diagnosis before age 40 years was 2.1 and was 1.5 for maternal diagnosis after age 70 years. For women with both an affected mother and at least one affected sister, the RR was 2.5.

However, most women with breast cancer do not have a family history of the disease in a first-degree relative, and less than 10% of breast cancers are estimated to be attributable to the inheritance of rare, highly penetrant, germline mutations in genes, [47] although this proportion is higher at younger ages of diagnosis. Mutations in BRCA1 and BRCA2 are responsible for most of these inherited breast cancers; mutations in p53 (causing Li-Fraumeni syndrome) and PTEN (causing Cowden syndrome) account for a small proportion of inherited breast cancers. Mutations in each of these genes occur in much less than 1% of the population.

Polymorphisms are usually defined as a sequence variant in a gene that occurs in more than 1% of alleles. Polymorphisms in genes that code for enzymes, receptors, or other proteins that act in metabolic pathways of potential relevance to breast cancer may influence the function of these proteins and thus create between-person differences in metabolic activity that may alter risk of breast cancer. Candidates include genes for carcinogen-metabolizing enzymes, steroid hormone-metabolizing enzymes, DNA repair genes, and receptors such as the estrogen and progesterone receptors. If these polymorphisms cause only modest increases in risk or confer risk only in conjunction with exposure to carcinogens, they would not cause noticeable familial aggregation. As these polymorphisms may be very common, their population-attributable risks may be large even if the RRs are modest.

The genome wide association studies have identified 6 breast cancer susceptibility alleles that are common in the population, but the clinical utility of such genetic risk is not yet clear.

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