TY - JOUR
T1 - BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers
AU - Maxwell, Kara N.
AU - Wubbenhorst, Bradley
AU - Wenz, Brandon M.
AU - De Sloover, Daniel
AU - Pluta, John
AU - Emery, Lyndsey
AU - Barrett, Amanda
AU - Kraya, Adam A.
AU - Anastopoulos, Ioannis N.
AU - Yu, Shun
AU - Jiang, Yuchao
AU - Chen, Hao
AU - Zhang, Nancy R.
AU - Hackman, Nicole
AU - D'Andrea, Kurt
AU - Daber, Robert
AU - Morrissette, Jennifer J.D.
AU - Mitra, Nandita
AU - Feldman, Michael
AU - Domchek, Susan M.
AU - Nathanson, Katherine L.
N1 - Funding Information:
Financial support for this work was provided by the Department of Defense (W81XWH- 13-1-0338, K.N.M.), National Institutes of Health (5T32GM008638-15, K.N.M.), Basser Center for BRCA at the University of Pennsylvania (K.L.N., S.M.D., R.D.), Konner Family Foundation (K.N.M.), Breast Cancer Research Foundation (K.L.N.), MacDonald Cancer Risk Evaluation Program (S.M.D.), Susan G Komen Foundation (S.M.D.) and Rooney Family Foundation (K.L.N., S.M.D.). Views and opinions of, and endorsements by the authors do not reflect those of the US Army or the Department of Defense. All work contained in this manuscript is original. We thank Louisa Pyle, M.D., Ph.D. and Kevin Nead, M.D. for helpful comments on the manuscript.
Funding Information:
Financial support for this work was provided by the Department of Defense (W81XWH-13-1-0338, K.N.M.), National Institutes of Health (5T32GM008638-15, K.N.M.), Basser Center for BRCA at the University of Pennsylvania (K.L.N., S.M.D., R.D.), Konner Family Foundation (K.N.M.), Breast Cancer Research Foundation (K.L.N.), MacDonald Cancer Risk Evaluation Program (S.M.D.), Susan G Komen Foundation (S.M.D.) and Rooney Family Foundation (K.L.N., S.M.D.). Views and opinions of, and endorsements by the authors do not reflect those of the US Army or the Department of Defense. All work contained in this manuscript is original. We thank Louisa Pyle, M.D., Ph.D. and Kevin Nead, M.D. for helpful comments on the manuscript.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-017-00388-9
DO - 10.1038/s41467-017-00388-9
M3 - Article
C2 - 28831036
AN - SCOPUS:85027871906
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 319
ER -
