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.

    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.

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

  • Author: Drapkin, Ronny

    Dana-Farber Cancer Institute, United States

  • Author: Fatima, Aquila

    Dana-Farber Cancer Institute, United States

  • Author: Tian, Ruiyang

    Dana-Farber Cancer Institute, United States

  • Author: Schwede, Matthew

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

  • Author: Alsop, Kathryn

    University of Melbourne, Australia

  • Author: Daniels, Kathryn E.

    Dana-Farber Cancer Institute, United States

  • Author: Piao, Huiying

    Dana-Farber Cancer Institute, United States

  • Author: Liu, Joyce

    Dana-Farber Cancer Institute, United States

  • Author: Etemadmoghadam, Dariush

    Cancer Genomics Program, Departments of Biochemistry and Pathology

  • Author: Miron, Alexander

    Dana-Farber Cancer Institute, United States

  • Author: Salvesen, Helga B.

    Department of Obstetrics and Gynecology, Haukeland University Hospital, Norway

  • Author: Mitchell, Gillian

    University of Melbourne, Australia

  • Author: DeFazio, Anna

    University of Sydney, Australia

  • Author: Quackenbush, John

    Dana-Farber Cancer Institute, United States

  • Author: Berkowitz, Ross S.

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

  • Author: Iglehart, J. Dirk

    Dana-Farber Cancer Institute, United States

  • Author: Bowtell, David D.L.

    Cancer Genomics Program, Departments of Biochemistry and Pathology

  • Author: Matulonis, Ursula A.

    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
Issue20
Pages5806-5815
ISSN1078-0432
DOIs
StatePublished
CitationsWeb of Science® Times Cited: 14
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