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 cancerassociated 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.

Comparative Analysis of Differentially Mutated Genes in Non-Muscle and Muscle-Invasive Bladder Cancer in the Chinese Population by Whole Exome Sequencing

“…Data from TCGA Research Network showed that TP53 (49%), MLL2 (27%), ARID1A (25%), KDM6A (24%), PIK3CA (20%), EP300 (15%), CDKN1A (14%), RB1 (13%), ERCC2(12%), FGFR3 (12%), STAG2 (11%) were the most frequently mutated genes in BCa ( The Cancer Genome Atlas Research Network, 2014 ). Data of 103 China BCa samples downloaded from International Cancer Genome Consortium (ICGC) database showed that TP53 (27.2%), KDM6A (24.3%), FGFR3 (16.5%), HRAS (15.5%), ERBB2 (13.6%), CREBBP (12.6%), ERCC2 (12.6%), ARID1A (11.7%), and XIRP2 (10.7%) were the top mutated genes ( Wang et al, 2020 ). One recent study conducted by Wang T et al performed targeted NGS in 32 BCa samples showed that FGFR3 (31.3%), KMT2D (18.8%), TP53 (12.5%), ARID1A (12.5%), AKT1 (12.5%), KDM6A (9.4%), STAG2 (9.4%), and LRP1B (9.4%) were the most frequently mutated genes in Chinese BCa patients ( Wang et al, 2020 ).…”

“…Data of 103 China BCa samples downloaded from International Cancer Genome Consortium (ICGC) database showed that TP53 (27.2%), KDM6A (24.3%), FGFR3 (16.5%), HRAS (15.5%), ERBB2 (13.6%), CREBBP (12.6%), ERCC2 (12.6%), ARID1A (11.7%), and XIRP2 (10.7%) were the top mutated genes ( Wang et al, 2020 ). One recent study conducted by Wang T et al performed targeted NGS in 32 BCa samples showed that FGFR3 (31.3%), KMT2D (18.8%), TP53 (12.5%), ARID1A (12.5%), AKT1 (12.5%), KDM6A (9.4%), STAG2 (9.4%), and LRP1B (9.4%) were the most frequently mutated genes in Chinese BCa patients ( Wang et al, 2020 ). Wu S. et al ( Wu et al, 2019 ) found FGFR3, TP53, PIK3CA, ZFP36L1, HRAS, and KDM6A were frequently mutated in Chinese BCa patients.…”

“…We also analyzed the sequencing data of 103 Chinese BCa samples download from ICGC database and found that TP53 mutation frequency was 26.3% (10/38) for NMIBC, and 27.7% (18/65) for MIBC. Targeted NGS results given by Wang T et al showed that TP53 mutation frequency was 25% (4/16) for NMIBC, and 0% (0/16) for MIBC in 32 Chinese BCa patients ( Wang et al, 2020 ). Meanwhile, we also checked frequently mutated genes in BCa samples from TCGA cohort, and identified that TP53 mutation frequency was 46.96% (193/411) for MIBC.…”

“…However, the molecular profile and mutational characteristics of NMIBC and MIBC at the genomic level in Chinese Han population have not been extensively investigated. As far as we know, there were only five studies investigating BCa genomic alterations in the Chinese population ( Gui et al, 2011 ; Guo et al, 2013 ; Pan et al, 2016 ; Wu et al, 2019 ; Wang et al, 2020 ), and none of them used WES instead of targeted NGS to systemically compare the characteristics of gene mutations in NMIBC and MIBC. In this study, using WES, we comprehensively examined, analyzed and compared the mutation spectra of nine NMIBC and 11 MIBC cases, including the frequencies of DNA-damage repair (DDR), tumor mutation burden (TMB), copy number alterations (CNA), and signatures.…”

Epidemiology, treatments, and related biomarkers of locally advanced or metastatic urothelial carcinoma in Chinese population: A scoping review

“…15,62,65 In addition, one study investigated RC48-ADC in HER2-positive patients evaluated by IHC and further confirmed by FISH. 11 In seven studies related to FGFR, five reported FGFR3 alterations, [68][69][70][71][72] one explored FGFR family alterations in UC patients, 73 and one investigated the landscape of FGF/ FGFR alterations in a large cohort of 12,737 cancer patients with a high prevalence of FGF/FGFR mutations | 15397 occurring in urinary tract cancer (52.7%, 145/275). 74 Various testing methods were applied, including sanger sequencing (n = 2), next-generation sequencing (NGS, n = 4), and whole-genome sequencing (n = 1).…”