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Novel somatic mutations identified by whole-exome sequencing in muscle-invasive transitional cell carcinoma of the bladder.

ABSTRACT: Transitional cell carcinoma (TCC) is the one of the most commonly observed types of cancer globally. The identification of novel disease-associated genes in TCC has had a significant effect on the diagnosis and treatment of bladder cancer; however, there may be a large number of novel genes that have not been identified. In the present study, the exomes of two individuals who were diagnosed with muscle-invasive TCC (MI-TCC) were sequenced to investigate potential variants. Subsequently, following algorithm and filter analysis, Sanger sequencing was used to validate the results of deep sequencing. Immunohistochemistry (IHC) was employed to observe the differences in HECT, C2 and WW domain-containing E3 ubiquitin protein ligase 1 (HECW1) protein expression between tumor tissues and para-carcinoma tissues. A total of 6 nonsynonymous mutation genes were identified in MI-TCC, identified as copine VII, RNA binding motif protein, X-linked-like 3, acyl-CoA synthetase medium-chain family member 2A, HECW1, zinc finger protein 273 and trichohyalin. Furthermore, 5 cases were identified to possess a HECW1 gene mutation in 61 MI-TCC specimens, and all of these were point mutations located at exon 11 on chromosome 7. The mutation categories of HECW1 had 4 missense mutations and 1 nonsense mutation. IHC revealed that HECW1 protein was expressed at significantly increased levels in MI-TCC compared with normal bladder urothelium (P<0.001). The present study provided a novel approach for investigating genetic changes in the MI-TCC exome, and identified the novel mutant gene HECW1, which may possess a significant role in the pathogenesis of TCC.

SUBMITTER: Pan H

PROVIDER: S-EPMC4734261 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Novel somatic mutations identified by whole-exome sequencing in muscle-invasive transitional cell carcinoma of the bladder.

Pan Huixing H Xu Xiaojian X Wu Deyao D Qiu Qiaocheng Q Zhou Shoujun S He Xuefeng X Zhou Yunfeng Y Qu Ping P Hou Jianquan J He Jun J Zhou Jian J

Oncology letters 20160108 2

Transitional cell carcinoma (TCC) is the one of the most commonly observed types of cancer globally. The identification of novel disease-associated genes in TCC has had a significant effect on the diagnosis and treatment of bladder cancer; however, there may be a large number of novel genes that have not been identified. In the present study, the exomes of two individuals who were diagnosed with muscle-invasive TCC (MI-TCC) were sequenced to investigate potential variants. Subsequently, followin ...[more]

PMID: 26893765

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Project description:Objective: To characterize the spectra of mutations in non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) in the Chinese population to identify any mutational features and find potential therapeutic targets. Materials and methods: We collected fresh bladder tumor samples from NMIBC (n = 9) and MIBC patients (n = 11) along with adjacent normal bladder tissue specimen and peripheral blood sample. Using whole exome sequencing (WES), we analyzed the mutation spectra of those NMIBC and MIBC bladder cancer (BCa) specimen. Results: Our results demonstrated that 95% of BCa patients (19/20) had varying degrees of driver gene mutations, FGFR3 (45%), KMT2D (40%), PIK3CA (35%), ARID1A (20%), EP300 (20%), KDM6A (20%), KMT2C (20%), and STAG2 (20%) were the most frequently mutated genes in BCa patients. NMIBC and MIBC exhibited different genomic alterations. FGFR3 (67%), PIK3CA (56%), and RHOB (44%) were the most frequently mutated genes in NMIBC patients. Of note, RHOB mutation only occurred in NMIBC, whereas mutations of KMT2D (55%), TP53 (36%) and KMT2B (27%) were frequently detected in MIBC, and TP53 and KMT2B mutation only occurred in MIBC. The frequency of mutations in DNA-damage repair (DDR) gene was higher in MIBC than that in NMIBC (91 vs 78%, 6.2 vs 2.4 gene mutations per patient). Copy number alterations (CNAs) occurred at more diverse chromosomal locations in NMIBC, but the CNA burden was higher in MIBC [9.01 (2.07-31.51) vs 4.98 (0.99-9.73) mutations/Mb]., the trend of which was consistent with the tumor mutation burden (TMB) [8.26 (4.63-21.84) vs 5.58 (3.87-9.58) mutations/Mb]. Among the current set of single-base substitution (SBS) signatures including SBS 1, 2, 5, 13, and 40, we identified one differently expressed signature between NMIBC and MIBC patients: SBS13. Conclusions: There were different gene mutational characteristics and signatures between NMIBC and MIBC in the Chinese population. Frequency of DDR, CNA burden and TMB were higher in MIBC. Our analysis revealed that several genes in NMIBC did not overlap with those reported in MIBC, suggesting that a fraction of NMIBC and MIBC likely developed secondary to different precursor lesions.

Dataset Information

Novel somatic mutations identified by whole-exome sequencing in muscle-invasive transitional cell carcinoma of the bladder.

Publications

Novel somatic mutations identified by whole-exome sequencing in muscle-invasive transitional cell carcinoma of the bladder.

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