Recurrence of Epigenetic Gene Mutations in Thymic Epithelial Carcinomas Revealed by Targeted Exome Sequencing of Cancer-Associated Genes.

7529 Background: Genetic alterations and etiology of thymic epithelial tumors (TET) are largely unknown, hampering development of effective targeted therapies for TET patients. Methods: TET patients enrolled in a clinical trial of molecularly-guided targeted therapies underwent exome capture sequencing of 197 cancer-associated genes. Somatic non-synonymous sequence variations including missense, nonsense, splice site mutations and indels were identified by comparative sequence analyses of tumor/blood paired samples. Results: Targeted exome capture sequencing of 78 advanced stage TETs (46 thymic carcinomas and 32 thymomas)/blood pairs revealed a total of 134 somatic non-synonymous sequence variations in 68 genes. Somatic non-synonymous sequence variations were found in 50% (39/78) of the TETs analyzed. Thymic carcinomas (67%; 31/46) showed higher incidence of somatic non-synonymous mutations than thymomas (25%; 8/32)(p=0.0002). TP53 (n = 13; 17%) was the most frequently mutated gene in TETs, and TP53 mutant patients showed poorer overall survival than TP53 wild-type patients (p < 0.0001). In thymic carcinomas, genes in epigenetic modification machinery [BAP1 (n = 6; 13%), SETD2 (n = 4; 9%), DNMT3A (n = 3; 7%), TET2 (n = 3; 7%), WT1 (n = 2; 4%), SMARCA4 (n = 2; 4%), and ASXL1 (n = 2; 4%)] were found recurrently mutated, whereas in thymomas, a preponderance of epigenetic gene mutations was not observed. Conclusions: Our results highlight the potential importance of epigenetic machinery in thymic carcinoma and indicate that substantial difference in genetic makeup exists between thymic carcinomas and thymomas. Targeting of epigenetic pathways may be of benefit to patients who carry those mutations.