TY - JOUR
T1 - Profiles of genomic instability in high-grade serous ovarian cancer predict treatment outcome
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.
N1 - ©2012 AACR
PY - 2012/10/15
Y1 - 2012/10/15
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.
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.
UR - http://www.scopus.com/inward/record.url?scp=84867536072&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-12-0857
DO - 10.1158/1078-0432.CCR-12-0857
M3 - Article
C2 - 22912389
AN - SCOPUS:84867536072
SN - 1078-0432
VL - 18
SP - 5806
EP - 5815
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 20
ER -