Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes

Endometrial cancer is the 6(th) most commonly diagnosed cancer among women worldwide, causing ~74,000 deaths annually (1). Serous endometrial cancers are a clinically aggressive subtype with a poorly defined genetic etiology (2-4). We used whole exome sequencing (WES) to comprehensively search for somatic mutations within ~22,000 protein-encoding genes among 13 primary serous endometrial tumors. We subsequently resequenced 18 genes that were mutated in more than one tumor, and/or were genes that formed an enriched functional grouping, from 40 additional serous tumors. We identified high frequencies of somatic mutations in CHD4 (17%), EP300 (8%), ARID1A (6%), TSPYL2 (6%), FBXW7 (29%), SPOP (8%), MAP3K4 (6%) and ABCC9 (6%). Overall, 36.5% of serous tumors had mutated a chromatin-remodeling gene and 35% had mutated a ubiquitin ligase complex gene, implicating the frequent mutational disruption of these processes in the molecular pathogenesis of one of the deadliest forms of endometrial cancer.