Ann Oncol 26(7): 1291-1299

Genetics of breast cancer: a topic in evolution

^{Divison of Medical Oncology, University of Washington, Seattle}

^{Divisions of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, USA}

^{Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, USA}

^{Correspondence to:} Dr Stacey Shiovitz, Seattle Cancer Care Alliance, 825 Eastlake Ave E., G4830, Seattle, WA 98109, USA. Tel: +1 206-288-6658; Email: ude.wu@ztivoihs

Received 2014 Jan 21; Revised 2014 Dec 2; Accepted 2014 Dec 31.

Copyright © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Abstract

A hereditary predisposition to breast cancer significantly influences screening and follow-up recommendations for high-risk women. However, in patients with a suggestive personal and/or family history, a specific predisposing gene is identified in <30% of cases. Up to 25% of hereditary cases are due to a mutation in one of the few identified rare, but highly penetrant genes (BRCA1, BRCA2, PTEN, TP53, CDH1, and STK11), which confer up to an 80% lifetime risk of breast cancer. An additional 2%–3% of cases are due to a mutation in a rare, moderate-penetrance gene (e.g. CHEK2, BRIP1, ATM, and PALB2), each associated with a twofold increase in risk. Prediction models suggest that there are unlikely to be additional yet to be identified high-penetrance genes. Investigation of common, low-penetrance alleles contributing to risk in a polygenic fashion has yielded a small number of suggestive single-nucleotide polymorphisms (SNPs), but the contributive risk of an individual SNP is quite small. Mutation testing is currently recommended for individual genes in the appropriate clinical setting where there is a high index of suspicion for a specific mutated gene or syndrome. Next-generation sequencing offers a new venue for risk assessment. At the present time, there are clear clinical guidelines for individuals with a mutation in a high-penetrance gene. Otherwise, standard models are used to predict an individual's lifetime risk by clinical and family history rather than genomic information.

Keywords: breast cancer, family history, genetics, screening, multiplex gene panels, BRCA

Abstract

references

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