BRCAness revisited

Abstract

Over the past 20 years, there has been considerable progress in our understanding of the biological functions of the BRCA1 and BRCA2 cancer susceptibility genes. This has led to the development of new therapeutic approaches that target tumours with loss-of-function mutations in either BRCA1 or BRCA2. Tumours that share molecular features of BRCA-mutant tumours — that is, those with 'BRCAness' — may also respond to similar therapeutic approaches. Several paradigm shifts require a reassessment of the concept of BRCAness, how this property is assayed and its relevance to our understanding of tumour biology and the treatment of cancer.

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Figure 1: DNA double-strand break repair by homologous recombination repair and BRCAness.
Figure 2: Biomarkers and cancer histologies associated with BRCAness and its potential clinical utility.

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Acknowledgements

The authors thank Breast Cancer Now, London, UK (formerly Breakthrough Breast Cancer and the Breast Cancer Campaign), Cancer Research UK; The Wellcome Trust, London, UK; The Breast Cancer Research Foundation, New York, USA; The Komen Foundation, Dallas, Texas, USA; and the University of California, San Francisco, USA for funding their work.

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Correspondence to Christopher J. Lord or Alan Ashworth.

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Competing interests

A.A. and C.J.L. are named inventors on patents describing the use of PARP inhibitors and as such stand to gain as part of the ICR 'Rewards to Inventors' Scheme.

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Supplementary information S1 (table)

Genes implicated in homologous recombination and/or PARP inhibitor sensitivity (XLSX 49 kb)

Glossary

Fanconi anaemia

(FA). A rare inherited disorder, normally diagnosed in children, in which the bone marrow does not produce key leukocyte lineages. Symptoms of FA include recurrent infections, a tendency to bleed easily and fatigue. Small skeletons and brown spots on the skin are also characteristics of FA, as is an enhanced predisposition to cancer.

Homologous recombination repair

(HRR). A form of DNA recombination often used to repair DNA double-strand breaks. HRR acts predominantly in the S and G2 phases of the cell cycle. Crucial proteins involved in mediating homologous recombination include those encoded by the BRCA1, BRCA2, RAD51 and partner and localizer of BRCA2 (PALB2) genes.

Loss of heterozygosity

(LOH). A situation in which an allele is lost, either by DNA recombination or by deletion, and the other allele is already deleted or mutated.

Maintenance therapy

A form of therapy used to enhance the overall effectiveness of a primary therapy. In most cases, maintenance therapy is given continuously after primary treatment to prevent or delay recurrence of disease.

Metagene signatures

Gene expression profiles derived from a panel of genes, as opposed to one gene, that correlate with clinical or biological phenotypes.

Non-homologous end joining

(NHEJ). A DNA repair mechanism that occurs throughout the cell cycle and directly ligates the ends of a DNA double-strand break (DSB) together. This process can cause the deletion or mutation of DNA sequences at or around the DSB site.

Odds ratio

A measure of the likelihood of an event happening in one group compared with a second group.

Panel sequencing

DNA sequencing that focuses on a subset of pre-defined genes or DNA regions, as opposed to sequencing of the entire exome or genome.

Pathological complete response

A clinical term defining the situation in which no histological signs of metastatic disease can be detected.

Synthetic lethal

Describes a form of genetic interaction. Two genes or proteins are synthetic lethal when inactivation of either one is compatible with cell viability but inactivation of both genes or proteins results in cell death.

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Lord, C., Ashworth, A. BRCAness revisited. Nat Rev Cancer 16, 110–120 (2016). https://doi.org/10.1038/nrc.2015.21

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