Breast Cancer Susceptibility Genes


Hereditary breast cancer is mainly attributed to loss‐of‐function mutations in and genes, which constitute the most important of the known breast cancer susceptibility genes in terms of high penetrance and clinical significance. Such mutations confer elevated breast and ovarian cancer risk, in comparison to the general population, while diagnosis usually occurs in young ages.

The evolution of sequencing technologies led to the identification of additional candidate breast cancer genes, most of which are considered to confer intermediate susceptibility. The majority of these genes are co‐players of genes in major repair mechanisms, which are essential in maintaining genomic integrity. Loss‐of‐function mutations identified in their loci are often associated with rare cancer syndromes that involve a broad spectrum of malignancies.

Genetic testing that involves the molecular analysis of hereditary breast cancer cases provides important information, able to orientate appropriate clinical decisions for the overall benefit of the individual carrying mutations in specific key genes.

Key Concepts

  • Hereditary breast cancer is associated with loss‐of‐function mutations in cancer‐predisposing genes.

  • BRCA1 and BRCA2 are the most commonly mutated genes accounting for 5–10% of hereditary breast cancer cases.

  • BRCA mutation carriers face a lifetime risk for both breast and ovarian cancer that can be as high as 82% and 44%, respectively.

  • A young age of breast cancer diagnosis is often observed in hereditary breast cancer cases.

  • At least 15 more genes have been associated with breast cancer susceptibility, most of which show intermediate penetrance and are rarely mutated.

  • Breast cancer genes encode for proteins that maintain genomic integrity through their catalytic role in DNA damage repair pathways (homologous recombination).

  • Molecular analysis of breast cancer predisposing genes is valuable for diagnosis, customised therapeutics and clinical management.

Keywords: breast cancer; BRCA1; BRCA2; PALB2; hereditary; germline mutations; genetic susceptibility

Figure 1. Distribution of breast cancer susceptibility genes. The majority of breast cancer cases are sporadic. Interestingly, 30% of the cases show familial aggregation, whereas one third of these cases are now known to be caused by germline loss‐of‐function mutations in high and moderate penetrance genes.


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Further Reading

Apostolou P and Fostira F (2013) Hereditary breast cancer: the era of new susceptibility genes. BioMed Research International 2013: 747318. DOI: 10.1155/2013/747318 Epub 2013 Mar 21.

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Walsh T and King MC (2007) Ten genes for inherited breast cancer. Cancer Cell 11 (2): 103–105.

Weitzel JN, Blazer KR, Macdonald DJ, Culver JO and Offit K (2011) CA genetics, genomics, and cancer risk assessment state of the art and future directions in the era of personalized medicine. Cancer Journal for Clinicians. DOI: 10.3322/caac.20128 [Epub ahead of print].

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Apostolou, Paraskevi, Vratimos, Athanassios, and Fostira, Florentia(Jan 2015) Breast Cancer Susceptibility Genes. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025847]