DNA Methylation Profiles of Ovarian Clear Cell Carcinoma.

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 IFNγ responses (P < 10-6). CONCLUSIONS: DNA methylation clusters in OCCC correlate with disease features and gene expression patterns among immune pathways. IMPACT: This work serves as a foundation for integrative analyses that better understand the complex biology of OCCC in an effort to improve potential for development of targeted therapeutics.

Authors:

JM Cunningham, SJ Winham, C Wang, B Weiglt, Z Fu, SM Armasu, BM McCauley, AH Brand, Y-E Chiew, E Elishaev, C Gourley, CJ Kennedy, A Laslavic, J Lester, A Piskorz, M Sekowska, JD Brenton, M Churchman, A DeFazio, R Drapkin, KM Elias, DG Huntsman, BY Karlan, M Köbel, J Konner, K Lawrenson, E Papaemmanuil, KL Bolton, F Modugno, EL Goode

Journal:

Cancer Epidemiol Biomarkers Prev

Citation info:

31(1):132-141

Publication date:

1st Jan 2022

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