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. Domchek; Katherine L. Nathanson

doi:10.1038/s41467-017-00388-9

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

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201 Scopus citations

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 language	English (US)
Article number	319
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00388-9
State	Published - Dec 1 2017

All Science Journal Classification (ASJC) codes

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

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Maxwell, K. N., Wubbenhorst, B., Wenz, B. M., De Sloover, D., Pluta, J., Emery, L., Barrett, A., Kraya, A. A., Anastopoulos, I. N., Yu, S., Jiang, Y., Chen, H., Zhang, N. R., Hackman, N., D'Andrea, K., Daber, R., Morrissette, J. J. D., Mitra, N., Feldman, M., ... Nathanson, K. L. (2017). BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers. Nature communications, 8(1), Article 319. https://doi.org/10.1038/s41467-017-00388-9

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title = "BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers",

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.",

author = "Maxwell, {Kara N.} and Bradley Wubbenhorst and Wenz, {Brandon M.} and {De Sloover}, Daniel and John Pluta and Lyndsey Emery and Amanda Barrett and Kraya, {Adam A.} and Anastopoulos, {Ioannis N.} and Shun Yu and Yuchao Jiang and Hao Chen and Zhang, {Nancy R.} and Nicole Hackman and Kurt D'Andrea and Robert Daber and Morrissette, {Jennifer J.D.} and Nandita Mitra and Michael Feldman and Domchek, {Susan M.} and Nathanson, {Katherine L.}",

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/s41467-017-00388-9",

language = "English (US)",

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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

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.

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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SN - 2041-1723

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JO - Nature communications

JF - Nature communications

IS - 1

M1 - 319

ER -

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

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