Profiles of Genomic Instability in High-Grade Serous Ovarian Cancer Predict Treatment Outcome
- 14 October 2012
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 18 (20), 5806-5815
- https://doi.org/10.1158/1078-0432.ccr-12-0857
Abstract
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. ©2012 AACR.Keywords
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This publication has 48 references indexed in Scilit:
- Integrated genomic analyses of ovarian carcinomaNature, 2011
- The genesis and evolution of high-grade serous ovarian cancerNature Reviews Cancer, 2010
- 53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA BreaksCell, 2010
- Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovaryThe Journal of Pathology, 2010
- Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancerNature Medicine, 2010
- Complex landscapes of somatic rearrangement in human breast cancer genomesNature, 2009
- Chromosomal instability determines taxane responseProceedings of the National Academy of Sciences of the United States of America, 2009
- Hallmarks of 'BRCAness' in sporadic cancersNature Reviews Cancer, 2004
- Germline BRCA1 Mutations and a Basal Epithelial Phenotype in Breast CancerJNCI Journal of the National Cancer Institute, 2003
- Repeated observation of breast tumor subtypes in independent gene expression data setsProceedings of the National Academy of Sciences of the United States of America, 2003