DNAMethylation Profiles of Ovarian Clear Cell Carcinoma

Julie M. Cunningham, Stacey J. Winham, Chen Wang, Britta Weiglt, Zhuxuan Fu, Sebastian M. Armasu, Bryan M. McCauley, Alison H. Brand, Yoke Eng Chiew, Esther Elishaev, Charlie Gourley, Catherine J. Kennedy, Angela Laslavic, Jenny Lester, Anna Piskorz, Magdalena Sekowska, James D. Brenton, Michael Churchman, Anna DeFazio, Ronny DrapkinKevin M. Elias, David G. Huntsman, Beth Y. Karlan, Martin Kobel, Jason Konner, Kate Lawrenson, Elli Papaemmanuil, Kelly L. Bolton, Francesmary Modugno, Ellen L. Goode

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background: Ovarian clear cell carcinoma (OCCC) is a rare ovarian cancer histotype that tends to be resistant to standard platinum-based chemotherapeutics. We sought to better understand the role of DNA methylation in clinical and biological subclassification of OCCC. Methods: We interrogated genome-wide methylation using DNA from fresh frozen tumors from 271 cases, applied nonsmooth nonnegative matrix factorization (nsNMF) clustering, and evaluated clinical associations and biological pathways. Results: Two approximately equally sized clusters that associated with several clinical features were identified. Compared with Cluster 2 (N=137), Cluster 1 cases (N=134) presented at a more advanced stage, were less likely to be of Asian ancestry, and tended to have poorer outcomes including macroscopic residual disease following primary debulking surgery (P < 0.10). Subset analyses of targeted tumor sequencing and IHC data revealed that Cluster 1 tumors showed TP53 mutation and abnormal p53 expression, and Cluster 2 tumors showed aneuploidy and ARID1A/PIK3CA mutation (P < 0.05). Cluster-defining CpGs included 1,388 CpGs residing within 200 bp of the transcription start sites of 977 genes; 38% of these genes (N = 369 genes) were differentially expressed across cluster in transcriptomic subset analysis (P < 10-4). Differentially expressed genes were enriched for six immune-related pathways, including IFNα and IFNg responses (P < 10-6). Conclusions: DNA methylation clusters in OCCC correlate with disease features and gene expression patterns among immune pathways.

Original languageEnglish
Pages (from-to)132-141
Number of pages10
JournalCancer Epidemiology Biomarkers and Prevention
Volume31
Issue number1
DOIs
StatePublished - Jan 2022

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