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

Abstract

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.

Clinico-Pathological Features and Immunohistochemical Comparison of p16, p53, and Ki-67 Expression in Muscle-Invasive and Non-Muscle-Invasive Conventional Urothelial Bladder Carcinoma

“…Given the importance of early diagnosis and treatment, p53 overexpression may be considered a good indication for more aggressive treatment. In spite of these results from many peer studies in different places over the world and during a few decades indicating a prognostic role of p53 immunostaining, our results revealed no significant difference in the p53 expression in MIBC when compared to NMIBC, which comes consistent with few other previous studies including the study conducted by Toll and Epstein reported no statistically significant difference between the invasive and non-invasive bladder tumors concerning IHC staining of p53 [45,46]. Tian and Epstein also studied 26 cases of bladder urothelial carcinomas for p53 and Ki-67 immunohistochemical expression noting that only 2 cases showed a significant increase of p53 staining expression in the invasive compared with the non-invasive tumors [47].…”

Comprehensive Collection of Whole-Slide Images and Genomic Profiles for Patients with Bladder Cancer

“…Traditionally, acquisition of a cancerous genome requires tumor resection, quality control and sequencing or panel detection, which is time-consuming, labor-intensive and expensive 12 . Identification of the genomic features of a tumor has significance for treatment and the prognosis 13 .…”

APOBEC3-mediated mutagenesis in cancer: causes, clinical significance and therapeutic potential

“…Since APOBEC3s can drive tumorigenesis through mutagenic and not mutagenic pathways, it could be beneficial to inhibit APOBEC3s in specific but likely numerous oncogenic contexts (Table 6 ). For example, APOBEC3 inhibitors could potentially prevent non-muscle invasive bladder cancer from progressing to muscle-invasive disease, which has a higher APOBEC3-induced mutation burden [ 1 , 200 ]. APOBEC3 inhibitors could also slow STING-dependent metastasis, especially in combination with emerging STING inhibitors [ 157 , 201 ].…”