BRCA Locus-specific Loss of Heterozygosity in Germline BRCA1 and BRCA2 Carriers

Overview

Journal Nat Commun

Specialty Biology

Date 2017 Aug 24

PMID 28831036

Citations 150

Authors

Kara N Maxwell

Bradley Wubbenhorst

Brandon M Wenz

Daniel De Sloover

John Pluta

Lyndsey Emery

Amanda Barrett

Adam A Kraya

Ioannis N Anastopoulos

Shun Yu

Yuchao Jiang

Hao Chen

Nancy R Zhang

Nicole Hackman

Kurt DAndrea

Robert Daber

Jennifer J D Morrissette

Nandita Mitra

Michael Feldman

Susan M Domchek

Katherine L Nathanson

Affiliations

Soon will be listed here.

Abstract

Complete loss of BRCA1 or BRCA2 function is associated with sensitivity to DNA damaging agents. However, not all BRCA1 and BRCA2 germline mutation-associated tumors respond. Herein we report analyses of 160 BRCA1 and BRCA2 germline mutation-associated breast and ovarian tumors. Retention of the normal BRCA1 or BRCA2 allele (absence of locus-specific loss of heterozygosity (LOH)) is observed in 7% of BRCA1 ovarian, 16% of BRCA2 ovarian, 10% of BRCA1 breast, and 46% of BRCA2 breast tumors. These tumors have equivalent homologous recombination deficiency scores to sporadic tumors, significantly lower than scores in tumors with locus-specific LOH (ovarian, P = 0.0004; breast P < 0.0001, two-tailed Student's t-test). Absence of locus-specific LOH is associated with decreased overall survival in ovarian cancer patients treated with platinum chemotherapy (P = 0.01, log-rank test). Locus-specific LOH may be a clinically useful biomarker to predict primary resistance to DNA damaging agents in patients with germline BRCA1 and BRCA2 mutations.Most tumours associated with germline BRCA1/BRCA2 loss of function mutations respond to DNA damaging agents, however, some do not. Herein, the authors identify that a subset of breast/ovarian tumors retain a normal allele, which is associated with decreased overall survival after DNA damage-inducing platinum chemotherapy.

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