Dataset Information

Identification of potential therapeutic targets in urothelial bladder carcinoma of Chinese population by targeted next-generation sequencing.

ABSTRACT: Patients with urothelial carcinoma (UC) of the bladder have a high risk of death in China. However, a lack of comprehensive molecular profiling in Chinese Han population hinders the development of targeted therapies for bladder cancer. In our present study, we collected fresh bladder tumors from low-grade (T1, N0, M0, G1) non-muscle invasive bladder cancer (NMIBC) patients (n = 16) and high-grade (T2-4, N0, M0, Gx) muscle-invasive bladder cancer (MIBC) patients (n = 16) with their paired normal bladder tissues, and subjected the total genomic DNAs to targeted next-generation sequencing (NGS) for 94 cancer-associated genes. NGS results showed that 30.9% of detected genes (29/94) was mutated in 32 urothelial carcinoma bladder tissues. Furthermore, our results and ICGC database showed that FGFR3, KMT2D, TP53, KDM6A, and ARID1A were the most frequently mutated genes in UC patients. Of note, NMIBC and MIBC displayed distinguishable genomic alterations. FGFR3, KMT2D, AKT1, ARID1A, and STAG2 were the most frequently mutated genes in NMIBC patients, whereas mutations of TP53, CREBBP, FGFR3, KDM6A, KMT2D, and ARID1A were frequently detected in MIBC. Intriguingly, gene ontology and clustering analysis revealed that these frequently mutated genes were highly enriched in signaling pathways responsible for cancer development. Taken together, the mutation frequency of genes associated with UC development in NMIBC and MIBC was screened out in Chinese Han population and elucidation of the related mechanisms provides theoretical basis and technical support for the development of early diagnosis and therapeutic strategies in UC.

SUBMITTER: Wang T

PROVIDER: S-EPMC7515499 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification of potential therapeutic targets in urothelial bladder carcinoma of Chinese population by targeted next-generation sequencing.

Wang Tao T Liu Zhengsheng Z Wang Xuegang X Bai Peide P Sun Anran A Shao Zhiqiang Z Luo Rongtuan R Wu Zhun Z Zhang Kaiyan K Li Wei W Xiao Wen W Duan Bo B Wang Yongfeng Y Chen Bin B Xing Jinchun J

Cancer biology & therapy 20200523 8

Patients with urothelial carcinoma (UC) of the bladder have a high risk of death in China. However, a lack of comprehensive molecular profiling in Chinese Han population hinders the development of targeted therapies for bladder cancer. In our present study, we collected fresh bladder tumors from low-grade (T1, N0, M0, G1) non-muscle invasive bladder cancer (NMIBC) patients (n = 16) and high-grade (T2-4, N0, M0, Gx) muscle-invasive bladder cancer (MIBC) patients (n = 16) with their paired normal ...[more]

PMID: 32449441

Similar Datasets

Project description:BackgroundMolecular characterization of nonmuscle invasive bladder cancer (NMIBC) may provide a biologic rationale for treatment response and novel therapeutic strategies.ObjectiveTo identify genetic alterations with potential clinical implications in NMIBC.Design, setting, and participantsPretreatment index tumors and matched germline DNA from 105 patients with NMIBC on a prospective Institutional Review Board-approved protocol underwent targeted exon sequencing analysis in a Clinical Laboratory Improvement Amendments-certified clinical laboratory.Outcome measurements and statistical analysisComutation patterns and copy number alterations were compared across stage and grade. Associations between genomic alterations and recurrence after intravesical bacillus Calmette-Guérin (BCG) were estimated using Kaplan-Meier and Cox regression analyses.Results and limitationsTERT promoter mutations (73%) and chromatin-modifying gene alterations (69%) were highly prevalent across grade and stage, suggesting these events occur early in tumorigenesis. ERBB2 or FGFR3 alterations were present in 57% of high-grade NMIBC tumors in a mutually exclusive pattern. DNA damage repair (DDR) gene alterations were seen in 30% (25/82) of high-grade NMIBC tumors, a rate similar to MIBC, and were associated with a higher mutational burden compared with tumors with intact DDR genes (p<0.001). ARID1A mutations were associated with an increased risk of recurrence after BCG (hazard ratio=3.14, 95% confidence interval: 1.51-6.51, p=0.002).ConclusionsNext-generation sequencing of treatment-naive index NMIBC tumors demonstrated that the majority of NMIBC tumors had at least one potentially actionable alteration that could serve as a target in rationally designed trials of intravesical or systemic therapy. DDR gene alterations were frequent in high-grade NMIBC and were associated with increased mutational load, which may have therapeutic implications for BCG immunotherapy and ongoing trials of systemic checkpoint inhibitors. ARID1A mutations were associated with an increased risk of recurrence after BCG therapy. Whether ARID1A mutations represent a predictive biomarker of BCG response or are prognostic in NMIBC patients warrants further investigation.Patient summaryAnalysis of frequently mutated genes in superficial bladder cancer suggests potential targets for personalized treatment and predictors of treatment response, and also may help develop noninvasive tumor detection tests.

Dataset Information

Identification of potential therapeutic targets in urothelial bladder carcinoma of Chinese population by targeted next-generation sequencing.

Publications

Identification of potential therapeutic targets in urothelial bladder carcinoma of Chinese population by targeted next-generation sequencing.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets