TY - JOUR
T1 - Molecular classification of epithelial ovarian cancer based on methylation profiling
T2 - Evidence for survival heterogeneity
AU - Bodelon, Clara
AU - Keith Killian, J.
AU - Sampson, Joshua N.
AU - Anderson, William F.
AU - Matsuno, Rayna
AU - Brinton, Louise A.
AU - Lissowska, Jolanta
AU - Anglesio, Michael S.
AU - Bowtell, David D.L.
AU - Doherty, Jennifer A.
AU - Ramus, Susan J.
AU - Talhouk, Aline
AU - Sherman, Mark E.
AU - Wentzensen, Nicolas
N1 - Funding Information:
This research was supported by the Intramural Research Program of the NCI. In addition, S.J. Ramus acknowledges support by the grant "Identifying Prognostic Markers and Therapeutic Targets for Serous Ovarian Cancer" (R01-CA172404), J.A. Doherty acknowledges support by the grant "Epidemiologic factors and survival by molecular subtypes of ovarian cancer" (R01-CA168758), and M.S. Anglesio acknowledges support by the Canadian Institutes of Health Research (CIHR) Proof of Principle (phase I) grant "PrOTYPE: An Enabling Technology to Improve Ovarian Cancer Care" and funding from the Janet D. Cottrelle Foundation Scholar Program administered by the BC Cancer Foundation.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - Purpose: Ovarian cancer is a heterogeneous disease that can be divided into multiple subtypes with variable etiology, pathogenesis, and prognosis. We analyzed DNA methylation profiling data to identify biologic subgroups of ovarian cancer and study their relationship with histologic subtypes, copy number variation, RNA expression data, and outcomes. Experimental Design: A total of 162 paraffin-embedded ovarian epithelial tumor tissues, including the five major epithelial ovarian tumor subtypes (high- and low-grade serous, endometrioid, mucinous, and clear cell) and tumors of low malignant potential were selected from two different sources: The Polish Ovarian Cancer study, and the Surveillance, Epidemiology, and End Results Residual Tissue Repository (SEER RTR). Analyses were restricted to Caucasian women. Methylation profiling was conducted using the Illumina 450K methylation array. For 45 tumors array copy number data were available. NanoString gene expression data for 39 genes were available for 61 high-grade serous carcinomas (HGSC). Results: Consensus nonnegative matrix factorization clustering of the 1,000 most variable CpG sites showed four major clusters among all epithelial ovarian cancers. We observed statistically significant differences in survival (log-rank test, P ¼ 9.1 107) and genomic instability across these clusters. Within HGSC, clustering showed three subgroups with survival differences (log-rank test, P ¼ 0.002). Comparing models with and without methylation subgroups in addition to previously identified gene expression subtypes suggested that the methylation subgroups added significant survival information (P ¼ 0.007). Conclusions: DNA methylation profiling of ovarian cancer identified novel molecular subgroups that had significant survival difference and provided insights into the molecular underpinnings of ovarian cancer. See related commentary by Ishak et al., p. 5729.
AB - Purpose: Ovarian cancer is a heterogeneous disease that can be divided into multiple subtypes with variable etiology, pathogenesis, and prognosis. We analyzed DNA methylation profiling data to identify biologic subgroups of ovarian cancer and study their relationship with histologic subtypes, copy number variation, RNA expression data, and outcomes. Experimental Design: A total of 162 paraffin-embedded ovarian epithelial tumor tissues, including the five major epithelial ovarian tumor subtypes (high- and low-grade serous, endometrioid, mucinous, and clear cell) and tumors of low malignant potential were selected from two different sources: The Polish Ovarian Cancer study, and the Surveillance, Epidemiology, and End Results Residual Tissue Repository (SEER RTR). Analyses were restricted to Caucasian women. Methylation profiling was conducted using the Illumina 450K methylation array. For 45 tumors array copy number data were available. NanoString gene expression data for 39 genes were available for 61 high-grade serous carcinomas (HGSC). Results: Consensus nonnegative matrix factorization clustering of the 1,000 most variable CpG sites showed four major clusters among all epithelial ovarian cancers. We observed statistically significant differences in survival (log-rank test, P ¼ 9.1 107) and genomic instability across these clusters. Within HGSC, clustering showed three subgroups with survival differences (log-rank test, P ¼ 0.002). Comparing models with and without methylation subgroups in addition to previously identified gene expression subtypes suggested that the methylation subgroups added significant survival information (P ¼ 0.007). Conclusions: DNA methylation profiling of ovarian cancer identified novel molecular subgroups that had significant survival difference and provided insights into the molecular underpinnings of ovarian cancer. See related commentary by Ishak et al., p. 5729.
UR - http://www.scopus.com/inward/record.url?scp=85072811784&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072811784&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-18-3720
DO - 10.1158/1078-0432.CCR-18-3720
M3 - Article
C2 - 31142506
AN - SCOPUS:85072811784
SN - 1078-0432
VL - 25
SP - 5937
EP - 5946
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 19
ER -