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

V. Abkevich, K. M. Timms, B. T. Hennessy, J. Potter, M. S. Carey, L. A. Meyer, K. Smith-Mccune, R. Broaddus, K. H. Lu, J. Chen, T. V. Tran, D. Williams, D. Iliev, S. Jammulapati, L. M. Fitzgerald, T. Krivak, J. A. Deloia, A. Gutin, G. B. Mills, J. S. Lanchbury

Research output: Contribution to journalArticle

246 Scopus citations

Abstract

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 (P10 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 (P10 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.

Original languageEnglish (US)
Pages (from-to)1776-1782
Number of pages7
JournalBritish Journal of Cancer
Volume107
Issue number10
DOIs
StatePublished - Nov 6 2012
Externally publishedYes

Keywords

  • DNA double-strand break repair
  • Homologous recombination deficiency
  • Loss of heterozygosity
  • Ovarian cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Abkevich, V., Timms, K. M., Hennessy, B. T., Potter, J., Carey, M. S., Meyer, L. A., Smith-Mccune, K., Broaddus, R., Lu, K. H., Chen, J., Tran, T. V., Williams, D., Iliev, D., Jammulapati, S., Fitzgerald, L. M., Krivak, T., Deloia, J. A., Gutin, A., Mills, G. B., & Lanchbury, J. S. (2012). Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. British Journal of Cancer, 107(10), 1776-1782. https://doi.org/10.1038/bjc.2012.451