Profiles of Genomic Instability in High-Grade Serous Ovarian Cancer Predict Treatment Outcome

Publication: Research - peer-reviewJournal article – Annual report year: 2012

  • Author: Wang, Zhigang C., United States

    Department of Cancer Biology, Dana-Farber Cancer Institute, United States

  • Author: Birkbak, Nicolai Juul

    Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet, 2800, Lyngby, Denmark

  • Author: Culhane, Aedín C., United States

    Biostatistics and Computational Biology, Dana-Faber Cancer Institute, United States

  • Author: Drapkin, Ronny, United States

    Department of Medical Oncology, Dana-Farber Cancer Institute, United States

  • Author: Fatima, Aquila, United States

    Department of Cancer Biology, Dana-Farber Cancer Institute, United States

  • Author: Tian, Ruiyang, United States

    Department of Cancer Biology, Dana-Farber Cancer Institute, United States

  • Author: Schwede, Matthew, United States

    Department of Biostatistics and Computational Biology,Dana-Farber Cancer Institute, United States

  • Author: Alsop, Kathryn, Australia

    Familial Cancer Centre, Peter MacCallum Cancer Centre and the University of Melbourne, Australia

  • Author: Daniels, Kathryn E., United States

    Department of Medical Oncology, Dana-Farber Cancer Institute, United States

  • Author: Piao, Huiying, United States

    Department of Medical Oncology, Dana-Farber Cancer Institute, United States

  • Author: Liu, Joyce, United States

    Department of Medical Oncology, Dana-Farber Cancer Institute, United States

  • Author: Etemadmoghadam, Dariush

    Cancer Genomics Program, Departments of Biochemistry and Pathology

  • Author: Miron, Alexander, United States

    Department of Cancer Biology, Dana-Farber Cancer Institute, United States

  • Author: Salvesen, Helga B., Norway

    12Department of Obstetrics and Gynecology, Haukeland University Hospital, Norway

  • Author: Mitchell, Gillian, Australia

    10Familial Cancer Centre, Peter MacCallum Cancer Centre and the University of Melbourne, Australia

  • Author: DeFazio, Anna, Australia

    11Department of Gynaecological Oncology and Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Australia

  • Author: Quackenbush, John, United States

    Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, United States

  • Author: Berkowitz, Ross S., United States

    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, United States

  • Author: Iglehart, J. Dirk, United States

    Department of Cancer Biology, Dana-Farber Cancer Institute, United States

  • Author: Bowtell, David D.L.

    Cancer Genomics Program, Departments of Biochemistry and Pathology

  • Author: Matulonis, Ursula A., United States

    Department of Medical Oncology, Dana-Farber Cancer Institute, United States

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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. ©2012 AACR.
Original languageEnglish
JournalClinical Cancer Research
Publication date2012
Volume18
Journal number20
Pages5806-5815
ISSN1078-0432
DOIs
StatePublished
CitationsWeb of Science® Times Cited: 11
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