Mutational Landscape of Bladder Cancer in Mexican Patients: KMT2D Mutations and chr11q15.5 Amplifications Are Associated with Muscle Invasion

Abstract

Bladder cancer (BC) is the most common neoplasm of the urinary tract, which originates in the epithelium that covers the inner surface of the bladder. The molecular BC profile has led to the development of different classifications of non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). However, the genomic BC landscape profile of the Mexican population, including NMIBC and MIBC, is unknown. In this study, we aimed to identify somatic single nucleotide variants (SNVs) and copy number variations (CNVs) in Mexican patients with BC and their associations with clinical and pathological characteristics. We retrospectively evaluated 37 patients treated between 2012 and 2021 at the National Cancer Institute—Mexico (INCan). DNA samples were obtained from paraffin-embedded tumor tissues and exome sequenced. Strelka2 and Lancet packages were used to identify SNVs and insertions or deletions. FACETS was used to determine CNVs. We found a high frequency of mutations in TP53 and KMT2D, gains in 11q15.5 and 19p13.11-q12, and losses in 7q11.23. STAG2 mutations and 1q11.23 deletions were also associated with NMIBC and low histologic grade.

Predicting response to cisplatin-based neoadjuvant chemotherapy for muscle-invasive bladder cancer: transcriptomic features outrank genomic biomarkers

“…4A). This frequency is consistent with previously reported in other MIBC cohorts 12,26,27 , highlighting their role as BC drivers.…”

“…The mutational landscape of our cohort was consistent with those found in other MIBC cohorts 12,26,27,56 . While mutations in genes such as TP53, ERCC2, RB1, ATM and FGFR3 are known to correlate with response to cisplatin-based NAC 57–63 , in our study, more SNVs in ERCC2, RB1 and ATM were found in R compared to NR, but no statistically significant differentiation was found 59,60,64–67 .…”

“…SCNVs play a crucial role in cancer development, progression and treatment resistance/sensitivity. Amplifications and deletions in genes frequently implicated in BC (E2F3amp, PPARGamp, MDM2amp, ERBB2amp, CDKN2Adel and RB1del) 12,27 occurred across the whole cohort. ERCC1amp and KDM6Adel have previously been identified for their significant role in response to platinum-based chemotherapy 28,29 .…”

Molecular Mechanisms of Tumor Progression and New Therapeutic Strategies for Urological Cancers

“…Perez-Montiel and colleagues have examined the genetic landscape of Mexican BC patients, a hitherto understudied population, and found a high frequency of mutations in TP53 and KMT2D, along with gains in 11q15.5 and 19p13.11-q12 and losses in 7q11.23. Furthermore, STAG2 mutations and 1q11.23 deletions were associated with NMIBC and a low histologic grade, which offers fresh perspectives for classifying BC subtypes [18].…”