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

Abstract

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 CCECs, and assessed the mutational spectrum of known and candidate driver genes in a large cohort of cases. Methods We whole exome sequenced paired tumor-normal DNAs from 16 CCECs (12 CCECs and the CCEC components of four mixed histology tumors). Twenty-two genes-of-interest were Sanger sequenced from another 47 CCECs. Microsatellite instability and stability (MSI and MSS) were determined by genotyping five 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 CCECs 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 eight mutations in TAF1, a gene with no known role in CCEC, localized to the putative histone acetyltransferase domain and included two recurrently mutated residues. Based on patterns of MSI and mutations in seven genes, subsets of CCECs molecularly resembled serous ECs (SECs) or endometrioid ECs (EECs). Conclusions Our findings demonstrate molecular similarities between CCECs and SECs and EECs, and implicate TAF1 as a novel candidate CCEC driver gene.

The significance of L1CAM expression in clear cell carcinoma of the endometrium

“…Our findings are different from other aspects of those studies, however, including one result that L1CAM expression is not associated with survival in non‐endometrioid carcinomas and another that high L1CAM expression is unassociated with recurrence rates in high‐risk endometrial carcinoma . Neither of the aforementioned studies had a component of clear cell carcinoma that is comparable in size to the present dataset, and this may explain some differences in the reported findings, especially given the known heterogeneity in this histotype …”

“…Although clear cell carcinoma is generally considered to be a clinically aggressive, ‘high risk’ cancer, reported patient outcomes have been markedly variable at every stage of disease, possibly reflecting an underlying biologic heterogeneity that is inherent to the histotype . Indeed, somatic mutation profiling of cases classified as clear cell carcinoma have shown them to be markedly heterogeneous at the molecular level, with subsets resembling serous carcinomas, endometrioid carcinoma, neither, or both . Furthermore, recent data suggests that molecular classifications may have prognostic significance in clear cell carcinoma, a finding that raises the future possibility of stratifying these patients upfront in a manner that directly influences their management.…”

“…9 Indeed, somatic mutation profiling of cases classified as clear cell carcinoma have shown them to be markedly heterogeneous at the molecular level, with subsets resembling serous carcinomas, endometrioid carcinoma, neither, or both. [10][11][12] Furthermore, recent data suggests that molecular classifications may have prognostic significance in clear cell carcinoma, 10 a finding that raises the future possibility of stratifying these patients upfront in a manner that directly influences their management. This possibility notwithstanding, there currently remains a notable dearth of routinely available phenotypic markers to facilitate this stratification.…”

Clear cell endometrial carcinoma and the TCGA classification

“…Study methods are reported in detail in the Data . Five studies with a total of 162 patients with CCC were included. The characteristics of the included studies are shown in Table .…”

Genetic landscape of clear cell endometrial cancer and the era of precision medicine

“…This tumor type was not included in the TCGA endometrial cancer study, and much less is known about the molecular drivers of this malignancy. The study by Le Gallo et al 2 in this issue of Cancer represents the largest effort to date to characterize the mutational landscape of CCEC. Whole exome sequencing was performed using paired tumor-normal DNA samples from 16 cases of CCEC to identify recurrently mutated genes.…”