Journal
CLINICAL CANCER RESEARCH
Volume 18, Issue 20, Pages 5806-5815Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-12-0857
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Funding
- Breast Cancer Research Foundation, New York, NY
- Susan F. Smith Center for Women's Cancers Program at Dana-Farber Cancer Institute
- Danish Council for Independent Research-Medical Sciences (FSS)
- Ovarian Cancer SPORE [P50 CA105009]
- Ovarian Cancer Research Fund
- Robert and Deborah First Fund
- U.S. Army Medical Research and Materiel Command [DAMD17-01-1-0729]
- US Department of Defense [W81XWH-08-1-0684, W81XWH-08-1-0685]
- Cancer Australia
- National Breast Cancer Foundation [509303]
- Peter MacCallum Cancer Centre Foundation
- Cancer Council Victoria
- Queensland Cancer Fund
- Cancer Council New South Wales
- Cancer Council South Australia
- Cancer Foundation of Western Australia
- Cancer Council Tasmania
- National Health and Medical Research Council of Australia (NHMRC)
- NHMRC
- The Norwegian Cancer Society
- The Research Council of Norway
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Purpose: High-grade serous cancer (HGSC) is the most common cancer of the ovary and is characterized by chromosomal instability. Defects in homologous recombination repair (HRR) are associated with genomic instability in HGSC, and are exploited by therapy targeting DNA repair. Defective HRR causes uniparental deletions and loss of heterozygosity (LOH). Our purpose is to profile LOH in HGSC and correlate our findings to clinical outcome, and compare HGSC and high-grade breast cancers. Experimental Design: We examined LOH and copy number changes using single nucleotide polymorphism array data from three HGSC cohorts and compared results to a cohort of high-grade breast cancers. The LOH profiles in HGSC were matched to chemotherapy resistance and progression-free survival (PFS). Results: LOH-based clustering divided HGSC into two clusters. The major group displayed extensive LOH and was further divided into two subgroups. The second group contained remarkably less LOH. BRCA1 promoter methylation was associated with the major group. LOH clusters were reproducible when validated in two independent HGSC datasets. LOH burden in the major cluster of HGSC was similar to triple-negative, and distinct from other high-grade breast cancers. Our analysis revealed an LOH cluster with lower treatment resistance and a significant correlation between LOH burden and PFS. Conclusions: Separating HGSC by LOH-based clustering produces remarkably stable subgroups in three different cohorts. Patients in the various LOH clusters differed with respect to chemotherapy resistance, and the extent of LOH correlated with PFS. LOH burden may indicate vulnerability to treatment targeting DNA repair, such as PARP1 inhibitors. Clin Cancer Res; 18(20); 5806-15. (C) 2012 AACR.
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