Somatic mutation profiles of clear cell endometrial tumors revealed by whole exome and targeted gene sequencing

• Published in: Cancer Vol. 123; no. 17; pp. 3261 - 3268
• Main Authors: Le Gallo, Matthieu, Rudd, Meghan L., Urick, Mary Ellen, Hansen, Nancy F., Zhang, Suiyuan, Lozy, Fred, Sgroi, Dennis C., Vidal Bel, August, Matias‐Guiu, Xavier, Broaddus, Russell R., Lu, Karen H., Levine, Douglas A., Mutch, David G., Goodfellow, Paul J., Salvesen, Helga B., Mullikin, James C., Bell, Daphne W.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.09.2017
• Subjects: adenocarcinoma; Adenocarcinoma, Clear Cell - genetics; Adenocarcinoma, Clear Cell - pathology; Aged; Analogies; Cancer; clear cell; Cohort Studies; DNA Mutational Analysis; Endometrial cancer; endometrial carcinoma; Endometrial Neoplasms - genetics; Endometrial Neoplasms - pathology; Endometrium; Exome; Female; Gene Expression Regulation, Neoplastic; Gene sequencing; Genes; Genome-Wide Association Study; Genotyping; Histology; Histone acetyltransferase; Histone Acetyltransferases - genetics; Humans; Immunoblotting - methods; Loads (forces); Microsatellite Instability; Middle Aged; Molecular Sequence Data; Mutation; Oncology; p53 Protein; Pathogenesis; Prognosis; Stability; TATA-Binding Protein Associated Factors - genetics; Transcription Factor TFIID - genetics; Tumors; uterine cancer; mutation; exome; uterine cancer; clear cell; endometrial cancer; adenocarcinoma; endometrial carcinoma
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.30745

BACKGROUND The molecular pathogenesis of clear cell endometrial cancer (CCEC), a tumor type with a relatively unfavorable prognosis, is not well defined. We searched exome‐wide for novel somatically mutated genes in CCEC and assessed the mutational spectrum of known and candidate driver genes in a large cohort of cases. METHODS We conducted whole exome sequencing of paired tumor‐normal DNAs from 16 cases of CCEC (12 CCECs and the CCEC components of 4 mixed histology tumors). Twenty‐two genes‐of‐interest were Sanger‐sequenced from another 47 cases of CCEC. Microsatellite instability (MSI) and microsatellite stability (MSS) were determined by genotyping 5 mononucleotide repeats. Results Two tumor exomes had relatively high mutational loads and MSI. The other 14 tumor exomes were MSS and had 236 validated nonsynonymous or splice junction somatic mutations among 222 protein‐encoding genes. Among the 63 cases of CCEC in this study, we identified frequent somatic mutations in TP53 (39.7%), PIK3CA (23.8%), PIK3R1 (15.9%), ARID1A (15.9%), PPP2R1A (15.9%), SPOP (14.3%), and TAF1 (9.5%), as well as MSI (11.3%). Five of 8 mutations in TAF1, a gene with no known role in CCEC, localized to the putative histone acetyltransferase domain and included 2 recurrently mutated residues. Based on patterns of MSI and mutations in 7 genes, CCEC subsets molecularly resembled serous endometrial cancer (SEC) or endometrioid endometrial cancer (EEC). CONCLUSION Our findings demonstrate molecular similarities between CCEC and SEC and EEC and implicate TAF1 as a novel candidate CCEC driver gene. Cancer 2017;123:3261‐8. © 2017 American Cancer Society. The objective of this study was to search exome‐wide for novel somatically mutated genes in clear cell endometrial cancers (ECs) and to assess the mutational spectrum of known and candidate driver genes in this tumor type. Our findings demonstrate the molecular similarities of some clear cell ECs to serous and endometrioid ECs, and implicate TAF1 as a novel candidate clear cell EC driver gene. See also pages 3216‐8.