Thymic carcinoma (TC) is a rare cancer whose genomic features have been examined in only a limited number of patients of European descent. Here, we characterized both genomic and epigenomic aberrations by whole exome sequencing, RNA sequencing, methylation array and copy number analyses in TCs from Asian patients and compared them with those in TCs from USA/European patients. Samples analyzed were 10 pairs of snap-frozen surgical specimens of cancerous and non-cancerous thymic tissue. All 10 cases were Japanese patients treated at the National Cancer Center Hospital, Japan, between 1994 and 2010. Mutational signature analysis indicated that the accumulation of age-related mutations drive TC development. We identified recurrent somatic mutations in TET2, CYLD, SETD2, TP53, FBXW7, HRAS and RB1, and no mutations in GTF2I, supporting the hypothesis that TC and thymoma are distinguishable by their genetic profiles. TCs with TET2 mutations had more hypermethylated genes than those without, and hyper-methylation was associated with downregulation of gene expression. Focal genome copy number gains, associated with elevated gene expression, were observed at the KIT (which is known to drive thymic carcinogenesis) and AHNAK2 gene loci. Taken together, the results suggest that the molecular processes leading to TC depend on the accumulation of genetic and epigenetic aberrations. In addition, epigenetic dysregulation as a result of the TET2 mutation was observed in a subset of TCs.
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