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

Cancer. 2017 Sep 1;123(17):3261-3268. doi: 10.1002/cncr.30745. Epub 2017 May 9.


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.

Keywords: adenocarcinoma; clear cell; endometrial cancer; endometrial carcinoma; exome; mutation; uterine cancer.

Publication types

  • Comparative Study

MeSH terms

  • Adenocarcinoma, Clear Cell / genetics*
  • Adenocarcinoma, Clear Cell / pathology
  • Aged
  • Cohort Studies
  • DNA Mutational Analysis
  • Endometrial Neoplasms / genetics*
  • Endometrial Neoplasms / pathology
  • Exome
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Genome-Wide Association Study
  • Histone Acetyltransferases / genetics*
  • Humans
  • Immunoblotting / methods
  • Microsatellite Instability
  • Middle Aged
  • Molecular Sequence Data
  • Mutation*
  • Prognosis
  • TATA-Binding Protein Associated Factors / genetics*
  • Transcription Factor TFIID / genetics*


  • TATA-Binding Protein Associated Factors
  • Transcription Factor TFIID
  • Histone Acetyltransferases
  • TATA-binding protein associated factor 250 kDa