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 journalArticle

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.

Original languageEnglish (US)
Article number319
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017
Externally publishedYes

Fingerprint

Loss of Heterozygosity
loci
Tumors
tumors
breast
Germ-Line Mutation
mutations
Neoplasms
Breast
Breast Neoplasms
Homologous Recombination
DNA
Proxy
deoxyribonucleic acid
Platinum
rank tests
Ovarian Neoplasms
Chemotherapy
biomarkers
Biomarkers

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Maxwell, K. N., Wubbenhorst, B., Wenz, B. M., De Sloover, D., Pluta, J., Emery, L., ... Nathanson, K. L. (2017). BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers. Nature Communications, 8(1), [319]. https://doi.org/10.1038/s41467-017-00388-9

BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers. / Maxwell, Kara N.; Wubbenhorst, Bradley; Wenz, Brandon M.; De Sloover, Daniel; Pluta, John; Emery, Lyndsey; Barrett, Amanda; Kraya, Adam A.; Anastopoulos, Ioannis N.; Yu, Shun; Jiang, Yuchao; Chen, Hao; Zhang, Nancy R.; Hackman, Nicole; D'Andrea, Kurt; Daber, Robert; Morrissette, Jennifer J.D.; Mitra, Nandita; Feldman, Michael; Domchek, Susan M.; Nathanson, Katherine L.

In: Nature Communications, Vol. 8, No. 1, 319, 01.12.2017.

Research output: Contribution to journalArticle

Maxwell, KN, Wubbenhorst, B, Wenz, BM, De Sloover, D, Pluta, J, Emery, L, Barrett, A, Kraya, AA, Anastopoulos, IN, Yu, S, Jiang, Y, Chen, H, Zhang, NR, Hackman, N, D'Andrea, K, Daber, R, Morrissette, JJD, Mitra, N, Feldman, M, Domchek, SM & Nathanson, KL 2017, 'BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers', Nature Communications, vol. 8, no. 1, 319. https://doi.org/10.1038/s41467-017-00388-9
Maxwell KN, Wubbenhorst B, Wenz BM, De Sloover D, Pluta J, Emery L et al. BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers. Nature Communications. 2017 Dec 1;8(1). 319. https://doi.org/10.1038/s41467-017-00388-9
Maxwell, Kara N. ; Wubbenhorst, Bradley ; Wenz, Brandon M. ; De Sloover, Daniel ; Pluta, John ; Emery, Lyndsey ; Barrett, Amanda ; Kraya, Adam A. ; Anastopoulos, Ioannis N. ; Yu, Shun ; Jiang, Yuchao ; Chen, Hao ; Zhang, Nancy R. ; Hackman, Nicole ; D'Andrea, Kurt ; Daber, Robert ; Morrissette, Jennifer J.D. ; Mitra, Nandita ; Feldman, Michael ; Domchek, Susan M. ; Nathanson, Katherine L. / BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers. In: Nature Communications. 2017 ; Vol. 8, No. 1.
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