Overview
Why This Dataset Matters
Clear cell endometrial cancer (CCEC) is a rare histological subtype associated with a relatively poor prognosis. Critically, it was not included in the original TCGA endometrial cancer study, meaning the molecular drivers of this subtype were almost entirely uncharacterized at the time of publication. This paper was described in an accompanying editorial as the largest effort to date to characterize the mutational landscape of CCEC.
Study Design — Two-Phase Approach
The study used a two-phase design: whole exome sequencing (WES) of paired tumor-normal DNAs from 16 cases of CCEC (12 pure CCECs and the CCEC components of 4 mixed histology tumors) to identify recurrently mutated genes. Twenty-two genes of interest were then Sanger-sequenced from another 47 cases of CCEC to more precisely define mutational frequency. MSI status was evaluated by genotyping 5 mononucleotide repeats. The total combined cohort was therefore 63 CCEC cases.
Key Quantitative Findings
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, the study identified frequent somatic mutations in: arxiv
The Novel Finding — TAF1
Five of eight mutations in TAF1, a gene with no known role in CCEC, localized to the putative histone acetyltransferase (HAT) domain and included two recurrently mutated residues. TAF1 is a component of the TFIID transcription factor complex — its discovery as a recurrently mutated gene in CCEC was a genuinely novel finding from this study. arxiv
Molecular Positioning of CCEC
The study compared the molecular profiles of the 63 CCECs to those of serous endometrial carcinomas (SECs) and endometrioid endometrial carcinomas (EECs). Seven genes in the prevalence screen (TP53, PPP2R1A, PTEN, ARID1A, KRAS, PIK3R1, and PIK3CA) are mutated at differential frequencies between SECs and EECs. The CCEC mutation frequencies were intermediate — TP53 and PPP2R1A mutations (enriched in SECs) as well as PIK3CA, PIK3R1, and ARID1A mutations (enriched in EECs) were all present in CCEC, positioning it genomically between the two established endometrial cancer types. medrxiv