Exome sequencing of serous endometrial tumors shows recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes
Reporter and Curator: Dr. Sudipta Saha, Ph.D
Endometrial cancer is the sixth most commonly diagnosed cancer in women worldwide, causing ~74,000 deaths annually. Serous endometrial cancers are a clinically aggressive subtype with a poorly defined genetic etiology2–4. Whole-exome sequencing was used to comprehensively search for somatic mutations within ~22,000 protein-encoding genes in 13 primary serous endometrial tumors. Subsequently 18 genes were resequenced, which were mutated in more than 1 tumor and/or were components of an enriched functional grouping, from 40 additional serous tumors.
The study provides new insights into the somatic mutations present in serous endometrial cancer exomes. However, it is important that the discovery screen is underpowered to detect all somatically mutated genes that drive serous tumors. For example, PIK3R1, which was previously found to be somatically mutated in 8% of serous endometrial tumors, was not somatically mutated in the tumors that formed the discovery screen. It was estimated that, for genes that are mutated in 8% of all serous endometrial cancers, a discovery screen of 12 tumors has 25% power to detect 2 mutated tumors and 63% power to detect 1 mutated tumor; for genes that are mutated in 20% of all serous endometrial cancers, the discovery screen had an estimated 72.5% power to detect 2 mutated tumors and 93% power to detect 1 mutated tumor. Massively parallel sequencing of additional cases will undoubtedly yield deeper insights into the mutational landscape of serous endometrial cancer.
Thus, it was reported as one of the first exome sequencing analyses of serous endometrial cancers, which are clinically aggressive tumors that have been poorly characterized genomically. These findings implicate the disruption of chromatin-remodeling and ubiquitin ligase complex genes in 50% of serous endometrial tumors and 35% of clear-cell endometrial tumors. High frequencies of somatic mutations in CHD4 (17%), EP300 (8%), ARID1A (6%), TSPYL2 (6%), FBXW7 (29%), SPOP (8%), MAP3K4 (6%) and ABCC9 (6%) were identified. The high frequency and specific distributions of mutations in CHD4, FBXW7 and SPOP strongly suggest that these are likely to be driver events in serous endometrial cancer. Overall, 36.5% of serous tumors had a mutated chromatin-remodeling gene, and 35% had a mutated ubiquitin ligase complex gene, implicating frequent mutational disruption of these processes in the molecular pathogenesis of one of the deadliest forms of endometrial cancer.