Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer

被引：591

作者：

Abkevich, V. ^{[1
]}

Timms, K. M. ^{[1
]}

Hennessy, B. T. ^{[2
,3
]}

Potter, J. ^{[1
]}

Carey, M. S. ^{[4
]}

Meyer, L. A. ^{[5
]}

Smith-McCune, K. ^{[6
]}

Broaddus, R. ^{[7
]}

Lu, K. H. ^{[8
]}

Chen, J. ^{[1
]}

Tran, T. V. ^{[1
]}

Williams, D. ^{[1
]}

Iliev, D. ^{[1
]}

Jammulapati, S. ^{[1
]}

FitzGerald, L. M. ^{[1
]}

Krivak, T. ^{[9
]}

DeLoia, J. A. ^{[10
]}

Gutin, A. ^{[1
]}

Mills, G. B. ^{[4
]}

Lanchbury, J. S. ^{[1
]}

机构：

[1] Myriad Genet Inc, Salt Lake City, UT USA

[2] Beaumont Hosp, Dept Med Oncol, Dublin 9, Ireland

[3] Royal Coll Surgeons Ireland, Dublin 2, Ireland

[4] Univ British Columbia, Dept Obstet & Gynecol, Vancouver, BC, Canada

[5] Univ Texas Med Sch, Dept Obstet Gynecol & Reprod Sci, Houston, TX USA

[6] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[8] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Houston, TX 77030 USA

[9] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA

[10] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Exercise Sci, Washington, DC USA

来源：

BRITISH JOURNAL OF CANCER | 2012年 / 107卷 / 10期

基金：

爱尔兰科学基金会;

关键词：

loss of heterozygosity; homologous recombination deficiency; ovarian cancer; DNA double-strand break repair; GERMLINE MUTATIONS; SOMATIC MUTATIONS; MUTANT-CELLS; DNA-REPAIR; BRCA1; SUSCEPTIBILITY; RESISTANCE; BREAST; CHEMOTHERAPY; INHIBITORS;

D O I：

10.1038/bjc.2012.451

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

BACKGROUND: Defects in BRCA1, BRCA2, and other members of the homologous recombination pathway have potential therapeutic relevance when used to support agents that introduce or exploit double-stranded DNA breaks. This study examines the association between homologous recombination defects and genomic patterns of loss of heterozygosity (LOH). METHODS: Ovarian tumours from two independent data sets were characterised for defects in BRCA1, BRCA2, and RAD51C, and LOH profiles were generated. Publically available data were downloaded for a third independent data set. The same analyses were performed on 57 cancer cell lines. RESULTS: Loss of heterozygosity regions of intermediate size were observed more frequently in tumours with defective BRCA1 or BRCA2 (P = 10(-11)). The homologous recombination deficiency (HRD) score was defined as the number of these regions observed in a tumour sample. The association between HRD score and BRCA deficiency was validated in two independent ovarian cancer data sets (P = 10(-5) and 10(-29)), and identified breast and pancreatic cell lines with BRCA defects. CONCLUSION: The HRD score appears capable of detecting homologous recombination defects regardless of aetiology or mechanism. This score could facilitate the use of PARP inhibitors and platinum in breast, ovarian, and other cancers. British Journal of Cancer (2012) 107, 1776-1782. doi:10.1038/bjc.2012.451 www.bjcancer.com Published online 9 October 2012 (C) 2012 Cancer Research UK

引用

页码：1776 / 1782

页数：7

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