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 non-smooth non-negative 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 to 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-values <0.10). Subset analyses of targeted tumor sequencing and immunohistochemical data revealed that Cluster 1 tumors showed TP53 mutation and abnormal p53 expression, and Cluster 2 tumors showed aneuploidy and ARID1A/PIK3CA mutation (p-values <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-values <10-4). Differentially expressed genes were enriched for six immune-related pathways, including interferon alpha and gamma responses (p-values < 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE185008 | GEO | 2021/12/10

REPOSITORIES: GEO