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

被引:0
作者
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. Domchek
Katherine L. Nathanson
机构
[1] Perelman School of Medicine at the University of Pennsylvania,Division of Hematology
[2] Perelman School of Medicine at the University of Pennsylvania,Oncology, Department of Medicine
[3] Perelman School of Medicine at the University of Pennsylvania,Division of Translational Medicine and Human Genetics, Department of Medicine
[4] Perelman School of Medicine at the University of Pennsylvania,Department of Pathology and Laboratory Medicine
[5] The Wharton School of University of Pennsylvania,Department of Medicine
[6] University of California-Davis,Department of Statistics
[7] Perelman School of Medicine at the University of Pennsylvania,Department of Statistics
[8] Perelman School of Medicine at the University of Pennsylvania,Department of Biostatistics, Epidemiology and Informatics
来源
Nature Communications | / 8卷
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摘要
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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