TY - JOUR

T1 - Profiles of Genomic Instability in High-Grade Serous Ovarian Cancer Predict Treatment Outcome

A1 - Wang,Zhigang C.

A1 - Birkbak,Nicolai Juul

A1 - Culhane,Aedín C.

A1 - Drapkin,Ronny

A1 - Fatima,Aquila

A1 - Tian,Ruiyang

A1 - Schwede,Matthew

A1 - Alsop,Kathryn

A1 - Daniels,Kathryn E.

A1 - Piao,Huiying

A1 - Liu,Joyce

A1 - Etemadmoghadam,Dariush

A1 - Miron,Alexander

A1 - Salvesen,Helga B.

A1 - Mitchell,Gillian

A1 - DeFazio,Anna

A1 - Quackenbush,John

A1 - Berkowitz,Ross S.

A1 - Iglehart,J. Dirk

A1 - Bowtell,David D.L.

A1 - Matulonis,Ursula A.

AU - Wang,Zhigang C.

AU - Birkbak,Nicolai Juul

AU - Culhane,Aedín C.

AU - Drapkin,Ronny

AU - Fatima,Aquila

AU - Tian,Ruiyang

AU - Schwede,Matthew

AU - Alsop,Kathryn

AU - Daniels,Kathryn E.

AU - Piao,Huiying

AU - Liu,Joyce

AU - Etemadmoghadam,Dariush

AU - Miron,Alexander

AU - Salvesen,Helga B.

AU - Mitchell,Gillian

AU - DeFazio,Anna

AU - Quackenbush,John

AU - Berkowitz,Ross S.

AU - Iglehart,J. Dirk

AU - Bowtell,David D.L.

AU - Matulonis,Ursula A.

PB - American Association for Cancer Research (A A C R)

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

U2 - 10.1158/1078-0432.CCR-12-0857

DO - 10.1158/1078-0432.CCR-12-0857

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 20

VL - 18

SP - 5806

EP - 5815

ER -