Somatic and germline genomic variation in thymic carcinomas

Background: Thymic carcinoma (TC) is a rare and aggressive neoplasm of thymic epithelial origin, with no currently available biomarkers to guide treatment or prognosis. In this study, we aimed at characterizing the genomic landscape of a cohort of TCs, at somatic and germline levels. Materials and methods: Whole-exome sequencing was carried out on 25 TC archival samples and 17 histologically normal adjacent tissues. Genomic characteristics and their association with clinical outcomes were assessed. Results: High tumor mutational burden (TMB) and microsatellite instability were present in 8% and ∼30% of the study cohort. Somatic mutations in 20 core genes of DNA damage response (DDR) were associated with high TMB (P = 0.005) and worse overall survival (OS) [hazard ratio 5.05 (95% confidence interval 1.49-17.20), P = 0.010]. Putative pathogenic variants in the core DDR genes were frequently detected in the germline as well (35%). Among somatic alterations, driver genes included POLE, MTOR, and ATR (12%). Notably, ∼30% of patients harbored mutations matching biomarkers of response to currently available therapies such as poly (ADP-ribose) polymerase inhibitors. Somatic copy number profiles were heterogeneous; however, several amplification and deletion events were identified as recurrent across tumors. Conclusions: TC appears to be a heterogeneous disease, exhibiting varying genomic alteration rates. Several somatic and germline aberrations, some of which have been reported in this article for the first time, warrant further investigation for their hinted prognostic value and clinical implications.