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

Abstract

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 etiology. We used whole-exome sequencing to comprehensively search for somatic mutations within ~22,000 protein-encoding genes in 13 primary serous endometrial tumors. We subsequently resequenced 18 genes, which were mutated in more than 1 tumor and/or were components of 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 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.

Figure 1. Somatic mutations in CHD4, FBXW7, and SPOP cluster within important functional domains of the encoded proteins

Schematic representation of the CHD4, FBXW7, and SPOP proteins showing the positions of individual somatic mutations identified among primary endometrial tumors relative to important functional domains. Mutations in serous (yellow boxes), clear cell (brown boxes), endometrioid (red boxes) and mixed histology (white boxes) endometrial tumors are indicated. (a) 50% of all CHD4 mutations localize within the ATPase/helicase and helicase domains (top). (b) The majority of FBXW7 mutations in endometrial cancer cluster within the WD repeats. The FBXW7-Glu65* and -Lys70fs*27 mutations (not displayed) are within an alternate isoform. (c) All SPOP mutations in endometrial cancer localized to the MATH domain. BTB domain, Broad-complex, Tramtrack and Bric-a-brac domain; D-domain, Dimerization domain; MATH, Meprin and TRAF Homology; NLS, nuclear localization signal; PHD, Plant Homeo Domain-type zinc fingers; WD repeats, tryptophan-aspartic acid repeats.

Figure 2. Oncoprint showing the distribution of nonsynonymous somatic mutations in ubiquitin ligase complex genes and chromatin-remodeling genes among 26 serous and 8 clear cell endometrial tumors, and in TP53, PPP2R1A, and PIK3CA among 26 serous tumors

Individual tumors are indicated by blue bars. Nonsynonymous somatic mutations are indicated by yellow bars. Only tumors that had somatically mutated the ubiquitin ligase complex genes and chromatin-remodeling genes are shown. Collectively, the two ubiquitin ligase complex genes that regulate ubiquitin (Ub) mediated proteolysis were mutated in 35% (18 of 52) of serous endometrial tumors and 22% (5 of 23) of clear cell endometrial tumors; the 11 chromatin-remodeling genes were mutated in 36.5% (19 of 52) of serous endometrial tumors and 22% (5 of 23) of clear cell endometrial tumors. (*) The PIK3CA mutation pattern was previously reported in Rudd et al .

Figure 3. Somatic mutations in the consensus cancer genes EP300, and ARID1A, relative to the functional domains of the encoded proteins

Schematic representation of the (a) p300 and (b) BAF250A proteins, showing the positions of individual somatic mutations identified among primary endometrial tumors. Mutations in serous (yellow boxes) and clear cell (brown boxes) endometrial tumors are distinguished. Known functional domains of each protein are indicated. ARID, AT-rich Interaction Domain; BD, Bromodomain; KIX, KIX domain; PHD, Plant Homeo Domain Finger; TAZ, zinc finger TAZ-type; ZZ, zinc finger ZZ type.