BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers

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 D'Andrea, Robert Daber, Jennifer J.D. Morrissette, Nandita Mitra, Michael Feldman, Susan M. DomchekKatherine L. Nathanson

Research output: Contribution to journalArticlepeer-review

89 Scopus citations


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.

Original languageEnglish (US)
Article number319
JournalNature communications
Issue number1
StatePublished - Dec 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy


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