| Cancer arises as a consequence of cumulative disruptions to cellular growth control, with Darwinian selection for those heritable changes which provide the greatest clonal advantage. These traits can be acquired and stably maintained by either genetic or epigenetic means. Alterations in the genome and epigenome could influence each other and cooperate to promote oncogenic transformation. Disruption of epigenomic control is pervasive in malignancy, and can be classified as an enabling characteristic of cancer cells, akin to genome instability and mutation. We examined epigenetic profiles of several human cancers, including ovarian, endometrial and clear cell renal cell carcinoma (ccRCC) in the context of other genomic alterations, as part of the Cancer Genome Atlas (TCGA) project. We found varying degrees of disease heterogeneity among tumors of the various cancer types studied. We found that endometrial cancer comprises several distinct molecular groups, with a serous-like subtype that is similar to serous ovarian cancer and basal-like breast cancer. We also identified important or potentially important epigenetically silenced genes and studied their clinical implications. BRCA1 is epigenetically silenced in 12% of serous ovarian cancer cases, and mutually exclusive with BRCA1/2 mutations. This epigenetic silencing is associated with worse prognosis. VHL epigenetic silencing in ccRCC is mutually exclusive with VHL mutation. Finally, we hypothesized that genetic variants in one gene that we found to be epigenetically silenced in serous ovarian cancer and differentially methylated among different ovarian cancer subtypes, HNF1B, would be associated with ovarian cancer risk in a subtype-specific way. We comprehensively mapped variation in HNF1B with respect to EOC risk. Different SNPs were associated with invasive serous (rs7405776 OR=1.13, p = 3.1 × 10-10) and clear cell (rs11651755 OR = 0.77, p = 1.6 × 10-8) ovarian cancers. Risk alleles for the serous subtype were associated with higher HNF1B promoter methylation in these tumors. Unmethylated, expressed HNF1B, primarily present in clear cell tumors, coincided with a CpG Island Methylator Phenotype (CIMP) affecting numerous other promoters throughout the genome. Different variants in HNF1B are associated with risk of serous and clear cell ovarian cancers; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different ovarian cancer histological subtypes. |
