BRCA1 and BRCA2: 1994 and beyond

Key Points

  • In the ten years since the discovery of BRCA1 and BRCA2, genetic testing for breast and ovarian cancer susceptibility has become integrated into the practice of clinical oncology.

  • Attempts to identify a third breast cancer susceptibility locus (BRCA3) have so far been unsuccessful. This is probably because no single gene can account for the remainder of families that show a high incidence of breast cancer that is not associated with BRCA1 or BRCA2.

  • In general, the genes that have been identified as being associated with hereditary breast cancer (BRCA1, BRCA2, TP53, CHK2 and ATM) are involved in the maintenance of genomic integrity and DNA repair.

  • The risk of developing cancer is not identical for all carriers of BRCA1 and BRCA2 mutations. Risk can be influenced by allelic heterogeneity, modifier genes, and environmental and hormonal cofactors.

Abstract

The discovery of the first gene associated with hereditary breast cancer, BRCA1, was anticipated to greatly increase our understanding of both hereditary and sporadic forms of breast cancer, and to lead to therapeutic and preventive breakthroughs. Much has been learned during the past decade about the genetic epidemiology of breast cancer, the ethnic distribution and clinical consequences of BRCA1 and BRCA2 mutations, and the central role of DNA repair in breast cancer susceptibility. The ability to translate this knowledge into novel treatments, however, remains elusive.

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Figure 1: BRCA1 and BRCA2 functional domains, and selected binding partners.
Figure 2: The BRCA1 network.

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Acknowledgements

Work in W.D.F.'s laboratory is funded by the US Army, the Susan G. Komen Breast Cancer Foundation and the Canadian Breast Cancer Alliance.

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Correspondence to Steven A. Narod.

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DATABASES

Cancer.gov

breast cancer

endometrial cancer

ovarian cancer

prostate cancer

Wilms' tumour

Entrez Gene

ATM

BARD1

BRCA1

BRCA2

CHK2

cyclin D1

cyclin E

EMSY

ER

ERBB2

KIP1

p53

RAD51

WAF1

OMIM

Fanconi anaemia

FURTHER INFORMATION

The Breast Cancer Information Core

The Breast Cancer Linkage Consortium

Glossary

MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION

A technique used to determine the copy number of multiple specific sequences in a single reaction. Two probes are hybridized to the target sequence and are joined together by ligation to make a copy of that sequence. The probes are designed so that all the products can be amplified using the same primer pair. The relative quantity of each product establishes the copy number of the target sequence.

A LU SEQUENCES

Short interspersed nuclear elements present at a high frequency in primate genomes. Alu sequences are amplified in the genome by retrotransposition. A complete Alu sequence is approximately 300 bp long and contains an A-rich region near the centre and a stretch of As at the 3′ end.

FOUNDER MUTATIONS

Specific mutations that appear repeatedly in ethnically defined groups because of a shared common ancestry and, typically, rapid population growth.

RAD51 FOCI

Discrete nuclear foci comprised of DNA-repair complexes that accumulate after endogenous or induced DNA damage. BRCA2 is a component of these foci and delivers RAD51 to the sites of DNA damage. BRCA1 might also be required to complete these foci.

PROTEASOME

An organelle that breaks down proteins that have been targeted for degradation by ubiquitylation (by having a ubiquitin tag added to the protein). Lack of regulation of proteasomal degradation leads, for example, to loss of control of the cell cycle and seems to be an important step in tumorigenesis.

RING-FINGER MOTIF

A motif comprised of cysteine and histidine residues interspaced with hydrophobic amino acids. Proteins that contain this motif usually have ubiquitin-ligase functions.

TWO-HIT MODEL OF TUMORIGENESIS

States that both alleles of a tumour-suppressor gene need to be inactivated to promote unregulated tumour-cell growth. A given allele could be inactivated due to inherited mutation (constitutional), somatic mutation or epigenetic silencing. Hereditary tumours would be caused by an inherited mutation and a somatic mutation; non-hereditary tumours would be the result of two somatic mutations.

BASAL PHENOTYPE

Describes a relatively rare subtype of breast cancer that can be defined by immunohistochemistry. These tumours express markers that are typically seen in normal basal breast and skin epithelium, such as cytokeratins 5 and 6. This phenotype is often associated with a poor outcome.

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Narod, S., Foulkes, W. BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer 4, 665–676 (2004). https://doi.org/10.1038/nrc1431

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