Somatic mutations in renal cell carcinomas from Chinese patients revealed by whole exome sequencing

Abstract

BackgroundWhile the somatic mutation profiles of renal cell carcinoma (RCC) have been revealed by several studies worldwide, the overwhelming majority of those were not derived from Chinese patients. The landscape of somatic alterations in RCC from Chinese patients still needs to be elucidated to determine whether discrepancies exist between Chinese patients and sufferers from other countries and regions.MethodsWe collected specimens from 26 Chinese patients with primary RCC, including 15 clear cell renal cell carcinoma (ccRCC) samples, 5 papillary renal cell carcinoma (PRCC) samples and 6 chromophobe renal cell carcinoma (ChRCC) samples. Genomic DNAs were isolated from paired tumor-normal tissues and subjected to whole exome sequencing (WES). Immunohistochemistry analysis was performed to detect the programmed death ligand 1 (PD-L1) expression in tumor tissues.ResultsA total of 1920 nonsynonymous somatic variants in exons and 86 mutations at splice junctions were revealed. The tumor mutation burden of ccRCC was significantly higher than that of ChRCC (P < 0.05). For both ccRCC and PRCC, the most frequent substitution in somatic missense mutations was T:A > A:T, which was different from that recorded in the COSMIC database. Among eight significantly mutated genes in ccRCC in the TCGA database, six genes were verified in our study including VHL (67%), BAP1 (13%), SETD2 (13%), PBRM1 (7%), PTEN (7%) and MTOR (7%). All the mutations detected in those genes had not been reported in ccRCC before, except for alterations in VHL and PBRM1. Regarding the frequently mutated genes in PRCC in our study, DEPDC4 (p.E293A, p.T279A), PNLIP (p.N401Y, p.F342L) and SARDH (p.H554Q, p.M1T) were newly detected gene mutations predicted to be deleterious. As the most recurrently mutated gene in ChRCC in the TCGA dataset, TP53 (p.R81Q) was somatically altered only in one ChRCC case in this study. The HIF-1 signaling pathway was the most affected pathway in ccRCC, while the PI3K-Akt signaling pathway was altered in all of the three RCC types. Membranous PD-L1 expression was positive in tumor cells from 6/26 (23%) RCC specimens. The PD-L1-positive rate was higher in RCC samples with the somatically mutated genes CSPG4, DNAH11, INADL and TMPRSS13 than in specimens without those (P < 0.05).ConclusionsUsing WES, we identified somatic mutations in 26 Chinese patients with RCC, which enriched the racial diversity of the somatic mutation profiles of RCC subjects, and revealed a few discrepancies in molecular characterizations between our study and published datasets. We also identified numerous newly detected somatic mutations, which further supplements the somatic mutation landscape of RCC. Moreover, 4 somatically mutated genes, including CSPG4, DNAH11, INADL and TMPRSS13, might be promising predictive factors of PD-L1-positive expression in RCC tumor cells.Electronic supplementary materialThe online version of this article (10.1186/s12935-018-0661-5) contains supplementary material, which is available to authorized users.

TUBB3 Is Associated with High-Grade Histology, Poor Prognosis, p53 Expression, and Cancer Stem Cell Markers in Clear Cell Renal Cell Carcinoma

“…A recent report has shown that racial differences may contribute to the diversity of genomic aberrations in cancer [28]. In Chinese RCC patients, there are a few discrepancies regarding somatic mutation between Chinese patients and published data sets, such as TCGA [29]. Another paper showed that racial differences affect the histological subtype in RCC [30].…”

Genomic Alterations of Renal Cell Carcinoma and Clinical Implications in the Chinese Population

“…Data of somatic mutations of RCC in Chinese patients was released by a small size study which collected 26 RCC samples. The results of this study showed different frequencies of significantly mutated genes to that of the TCGA, and detected many mutations that were not reported previously [7]. This variation of genomic landscape of RCC in different populations called for research on RCC genomic aberrations in different races.…”

Cell Polarity Protein Pals1-Associated Tight Junction Expression Is a Favorable Prognostic Marker in Clear Cell Renal Cell Carcinoma

“…PATJ protein was originally identified localized in the tight junctions of epithelial cells (Bhat et al, 1999;Céline et al, 2002;Yoko et al, 2002) and was a novel regulatory element of the polycystin-2 (PC2) channel and involved in autosomal dominant polycystic kidney disease (ADPKD) (Duning et al, 2010). A previous study reported a PATJ somatic mutation in two of the three PD-L1-positive ccRCC cases (Wang et al, 2018); thus, suggesting that PATJ might be a promising predictive factor for PD-L1 expression in ccRCC cells. However, to date, there is no study reporting PATJ expression in ccRCC, to the best of our knowledge.…”