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Inherited Mutations in Breast Cancer Genes—Risk and Response

  • Andrew Y. Shuen
  • William D. FoulkesEmail author
Article

Abstract

Germ-line mutations in BRCA1 and BRCA2 confer a high risk of developing breast cancer. They account, however, for only 40% of strongly familial breast cancer cases. Intensive genome-wide searches for other highly-penetrant BRCA genes that, individually account for a sizeable fraction of the remaining heritability has not identified any plausible candidates. The “missing heritability” is thought to be due to cumulative effects of susceptibility alleles associated with low to moderate penetrance, in accordance with a polygenic model of inheritance. In addition, a large number of individually very rare, highly penetrant variants could account for part of the gap. Meanwhile, an understanding of the function of BRCA1 and BRCA2 in the DNA damage response pathway has lead to the identification of a number of breast cancer susceptibility genes including PALB2, CHEK2, ATM and BRIP1, all of which interact directly or indirectly with BRCA1 or BRCA2. Knowledge of how BRCA1 and BRCA2 maintain genomic integrity has also led the development of novel targeted therapies. Here we summarize the recent advances made in the understanding of the functions of these two genes, as well as the risks and responses associated with mutations in these and other breast cancer susceptibility genes.

Keywords

BRCA1 BRCA2 Breast cancer susceptibility genes PARP inhibitors Cisplatin 

Abbreviations

ATM

Ataxia telangiectasia mutated

BRCA1

Breast cancer susceptibility gene 1

BRCA2

Breast cancer susceptibility gene 2

BRIP1

BRCA1-interacting protein 1

CtBP

C terminal binding protein

DSB

Double strand break

ER

Estrogen receptor

GWAS

Genome-wide association study

HER2

Human epidermal growth factor receptor

HR

Homologous repair

MRN

Mre11–Rad50–Nbs1

OR

Odds ratio

PALB2

Partner and localizer of BRCA2

PARP

Poly (ADP-ribose) polymerase

pCR

Pathologic complete response

PR

Progesterone receptor

RING

Really interesting new gene

SNP

Single nucleotide polymorphism

SUMO

Small ubiquitin-like modifier

TNBC

Triple negative breast cancer

Notes

Acknowledgments

We thank Marc Tischkowitz MB.BCh. Ph.D for helpful comments.

Work carried out in Dr. Foulkes’ laboratory is supported by Susan G. Komen for the Cure.

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Medical GeneticsMcGill University Health CentreMontrealCanada
  2. 2.Program in Cancer Genetics, Departments of Oncology and Human Genetics, Gerald Bronfman Centre for Clinical Research in OncologyMcGill UniversityMontrealCanada
  3. 3.Department of Medical Genetics and Lady Davis InstituteJewish General HospitalMontrealCanada

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