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Mutational analysis of Ras hotspots in patients with urothelial carcinoma of the bladder.

ABSTRACT: BACKGROUND:Mutational activation of Ras genes is established as a prognostic factor for the genesis of a constitutively active RAS-mitogen activated protein kinase pathway that leads to cancer. Heterogeneity among the distribution of the most frequent mutations in Ras isoforms is reported in different patient populations with urothelial carcinoma of the bladder (UCB). AIM:To determine the presence/absence of mutations in Ras isoforms in patients with UCB in order to predict disease outcome. METHODS:This study was performed to determine the mutational spectrum at the hotspot regions of H-Ras, K-Ras and N-Ras genes by polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing followed by their clinical impact (if any) by examining the relationship of mutational spectrum with clinical histopathological variables in 87 UCB patients. RESULTS:None of the 87 UCB patients showed point mutations in codon 12 of H-Ras gene; codon 61 of N-Ras gene and codons 12, 13 of K-Ras gene by PCR-RFLP. Direct DNA sequencing of tumor and normal control bladder mucosal specimens followed by Blastn alignment with the reference wild-type sequences failed to identify even one nucleotide difference in the coding exons 1 and 2 of H-Ras, N-Ras and K-Ras genes in the tumor and control bladder mucosal specimens. CONCLUSION:Our findings on the lack of mutations in H-Ras, K-Ras and N-Ras genes could be explained on the basis of different etiological mechanisms involved in tumor development/progression, inherent genetic susceptibility, tissue specificity or alternative Ras dysfunction such as gene amplification and/or overexpression in a given cohort of patients.

SUBMITTER: Tripathi K

PROVIDER: S-EPMC7443835 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Mutational analysis of <i>Ras</i> hotspots in patients with urothelial carcinoma of the bladder.

Tripathi Kiran K Goel Apul A Singhai Atin A Garg Minal M

World journal of clinical oncology 20200801 8

<h4>Background</h4>Mutational activation of <i>Ras</i> genes is established as a prognostic factor for the genesis of a constitutively active RAS-mitogen activated protein kinase pathway that leads to cancer. Heterogeneity among the distribution of the most frequent mutations in <i>Ras</i> isoforms is reported in different patient populations with urothelial carcinoma of the bladder (UCB).<h4>Aim</h4>To determine the presence/absence of mutations in <i>Ras</i> isoforms in patients with UCB in or ...[more]

PMID: 32879848

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Project description:BackgroundDifferent genomic characterization in urothelial carcinoma (UC) by site of origin may imply contrasting therapeutic opportunities and pathogenetic mechanisms. The aim of this study was to investigate whether differences between upper tract UC (UTUC) and UC of the bladder (UCB) result from intrinsic biological diversity.Materials and methodsWe prospectively sequenced 118 tumors and matched blood DNA from Chinese patients with UC using next-generation sequencing techniques, including 45 UTUC and 73 UCB. Two hundred twenty-six patients with UTUC and 350 patients with UCB for The Cancer Genome Atlas were acquired from the cbioportal.ResultsThere were marked disparities in the mutational landscape for UC according to race and site of origin. Signature 22 for exposure to aristolochic acid was only observed in the UTUC cohort. Conversely, signature 6 for defective DNA mismatch repair only existed in the UCB cohort. Compared with UCB, UTUC had higher clonal and subclonal mutation numbers. TP53, PIK3CA, and FGFR3 mutations may be the driver genes for UTUC, whereas for UCB, the driver gene may be BRCA1. Patients with UTUC had lower PD-L1 than those with UCB. There was no significant difference in the number of DDR mutations, copy number variation counts, and tumor mutational burden between UTUC and UCB.ConclusionUTUC and UCB exhibit significant differences in the prevalence of genomic landscape and carcinogenesis. Consequently, molecular subtypes differ according to location, and these results may imply the site-specific management of patients with urothelial carcinoma. Mutational signature may be used as a screening tool to assist clinical differential diagnosis between UTUC and UCB.Implications for practiceThis study's findings lay the foundation for a deeper understanding of distinct molecular mechanisms and similar treatment opportunities between upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) and had important implications for the site-specific management of patients with urothelial carcinoma. A comprehensive understanding of the biology of UTUC and UCB is needed to identify new drug targets in order to improve clinical outcomes.

Dataset Information

Mutational analysis of Ras hotspots in patients with urothelial carcinoma of the bladder.

Publications

Mutational analysis of <i>Ras</i> hotspots in patients with urothelial carcinoma of the bladder.

Similar Datasets

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