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J Pathol. 2017 Jun;242(2):165-177. doi: 10.1002/path.4890. Epub 2017 Apr 27.

Bi-allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer.

Author information

1
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2
Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.
3
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
5
Department of Radiation Oncology, Yale, New Haven, CT, USA.
6
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
7
Department of Systems Biology, Harvard Medical School, Boston, MA, USA.

Abstract

Homologous recombination (HR) DNA repair-deficient (HRD) breast cancers have been shown to be sensitive to DNA repair targeted therapies. Burgeoning evidence suggests that sporadic breast cancers, lacking germline BRCA1/BRCA2 mutations, may also be HRD. We developed a functional ex vivo RAD51-based test to identify HRD primary breast cancers. An integrated approach examining methylation, gene expression, and whole-exome sequencing was employed to ascertain the aetiology of HRD. Functional HRD breast cancers displayed genomic features of lack of competent HR, including large-scale state transitions and specific mutational signatures. Somatic and/or germline genetic alterations resulting in bi-allelic loss-of-function of HR genes underpinned functional HRD in 89% of cases, and were observed in only one of the 15 HR-proficient samples tested. These findings indicate the importance of a comprehensive genetic assessment of bi-allelic alterations in the HR pathway to deliver a precision medicine-based approach to select patients for therapies targeting tumour-specific DNA repair defects. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

KEYWORDS:

BRCAness; DNA repair; RAD51; homologous recombination-deficient; mutation

PMID:
28299801
PMCID:
PMC5516531
DOI:
10.1002/path.4890
[Indexed for MEDLINE]
Free PMC Article

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