Journal article
Profiles of Genomic Instability in High-Grade Serous Ovarian Cancer Predict Treatment Outcome
Dana-Farber Cancer Institute1
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark2
Department of Systems Biology, Technical University of Denmark3
Dana-Faber Cancer Institute4
University of Melbourne5
Haukeland University Hospital6
University of Sydney7
Brigham and Women’s Hospital8
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.
Language: | English |
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Publisher: | American Association for Cancer Research |
Year: | 2012 |
Pages: | 5806-5815 |
ISSN: | 15573265 and 10780432 |
Types: | Journal article |
DOI: | 10.1158/1078-0432.CCR-12-0857 |
DNA Copy Number Variations Disease-Free Survival Female Gene Expression Regulation, Neoplastic Genomic Instability Humans Loss of Heterozygosity Neoplasm Grading Neoplasms, Cystic, Mucinous, and Serous Ovarian Neoplasms Polymorphism, Single Nucleotide Precision Medicine Predictive Biomarkers and Personalized Medicine Prognosis Treatment Outcome