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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.

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