Molecular classification of epithelial ovarian cancer based on methylation profiling: Evidence for survival heterogeneity

Clara Bodelon, J. Keith Killian, Joshua N. Sampson, William F. Anderson, Rayna Matsuno, Louise A. Brinton, Jolanta Lissowska, Michael S. Anglesio, David D.L. Bowtell, Jennifer A. Doherty, Susan J. Ramus, Aline Talhouk, Mark E. Sherman, Nicolas Wentzensen

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5937-5946
Number of pages10
JournalClinical Cancer Research
Volume25
Issue number19
DOIs
StatePublished - Oct 1 2019

Fingerprint

Ovarian Neoplasms
Methylation
Survival
DNA Fingerprinting
DNA Methylation
Cluster Analysis
Neoplasms
Carcinoma
Gene Expression
Genomic Instability
Paraffin
Epidemiology
Research Design
Epithelium
Ovarian epithelial cancer
RNA
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Bodelon, C., Keith Killian, J., Sampson, J. N., Anderson, W. F., Matsuno, R., Brinton, L. A., ... Wentzensen, N. (2019). Molecular classification of epithelial ovarian cancer based on methylation profiling: Evidence for survival heterogeneity. Clinical Cancer Research, 25(19), 5937-5946. https://doi.org/10.1158/1078-0432.CCR-18-3720

Molecular classification of epithelial ovarian cancer based on methylation profiling : Evidence for survival heterogeneity. / Bodelon, Clara; Keith Killian, J.; Sampson, Joshua N.; Anderson, William F.; Matsuno, Rayna; Brinton, Louise A.; Lissowska, Jolanta; Anglesio, Michael S.; Bowtell, David D.L.; Doherty, Jennifer A.; Ramus, Susan J.; Talhouk, Aline; Sherman, Mark E.; Wentzensen, Nicolas.

In: Clinical Cancer Research, Vol. 25, No. 19, 01.10.2019, p. 5937-5946.

Research output: Contribution to journalArticle

Bodelon, C, Keith Killian, J, Sampson, JN, Anderson, WF, Matsuno, R, Brinton, LA, Lissowska, J, Anglesio, MS, Bowtell, DDL, Doherty, JA, Ramus, SJ, Talhouk, A, Sherman, ME & Wentzensen, N 2019, 'Molecular classification of epithelial ovarian cancer based on methylation profiling: Evidence for survival heterogeneity', Clinical Cancer Research, vol. 25, no. 19, pp. 5937-5946. https://doi.org/10.1158/1078-0432.CCR-18-3720
Bodelon, Clara ; Keith Killian, J. ; Sampson, Joshua N. ; Anderson, William F. ; Matsuno, Rayna ; Brinton, Louise A. ; Lissowska, Jolanta ; Anglesio, Michael S. ; Bowtell, David D.L. ; Doherty, Jennifer A. ; Ramus, Susan J. ; Talhouk, Aline ; Sherman, Mark E. ; Wentzensen, Nicolas. / Molecular classification of epithelial ovarian cancer based on methylation profiling : Evidence for survival heterogeneity. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 19. pp. 5937-5946.
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abstract = "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.",
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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

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.

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