RB1 and TP53 co-mutations correlate strongly with genomic biomarkers of response to immunity checkpoint inhibitors in urothelial bladder cancer

Abstract

Background Muscle invasive urothelial bladder carcinoma (MIBC) present RB1 and TP53 somatic alterations in a variable percentage of tumors throughout all molecular subtypes. MIBCs with neuroendocrine features have a high response rate to immunity checkpoint inhibitors (ICIs). Whether the presence of somatic co-alterations in these 2 genes in MIBCs is relevant to their responsiveness to ICIs is not known. Methods The potential correlation of different genomic biomarkers of response to ICIs like tumor mutational burden (TMB), single nucleotide variants (SNV) predicted neoantigens, DNA damage response (DDR) genes, DNA somatic signatures and TILs infiltrate was explored in patients with somatic co-alterations in RB1 and TP53 (RB1&TP53) as compared with patients with no alterations in any (double wild type, DWT) or with alterations in just one of the 2 genes. The Cancer Genome Atlas (TCGA) pancancer BLCA dataset of cystectomy specimens (n = 407) with mutation, copy number alterations and transcriptomic (RNA sequencing) data as well as the IMVigor 210 study (n = 348) of metastatic urothelial bladder cancers treated with atezolizumab (PD-L1 inhibitor) with clinical response data containing transcriptomic (RNA sequencing), along with a subset (n = 274) with mutation and copy number data were used for this purpose. A novel tumor microenvironment metascore (TMM) was developed based in a LASSO regularized Cox model with predictive and prognostic ability. Results Samples with co-altered RB1&TP53: a) were enriched in immunity effectors (CD8 cytotoxic lymphocytes, NK cells) and display higher scores of a T cell inflamed signature; b) have a higher TMB, higher number of SNV predicted neoantigens and higher TILs fractions; c) have a higher number of DDR mutated and deep deleted DDR genes; d) have DNA somatic signatures 2 and 13 related to APOBEC mutagenesis. Using the IMVigor 210 dataset, RB1&TP53 samples had the highest response rate to atezolizumab and a strong correlation with TMB and TMM. The consensus molecular subtype classification in the IMVigor 210 dataset showed a significant correlation with both the response to treatment (p = 0.001, Chisquare) and the presence of RB1 and TP53 genomic alterations (p < 0.001, Chisquare). Conclusions RB1&TP53 co-alterations are strongly associated with genomic biomarkers of response to ICIs in MIBCs.

Epstein–Barr Virus—Associated Malignancies and Immune Escape: The Role of the Tumor Microenvironment and Tumor Cell Evasion Strategies

“…However, it is noteworthy that ARID1A aberrations were reported in EBV-associated as well as in EBV-negative GC subtypes [106]. Lower frequencies of TP53 mutations that usually show a positive correlation with higher mutational burden have been reported for EBV-positive NPC, GC, BL and PTLD [105,[107][108][109][110][111] despite that the p53 pathway is frequently deregulated in these diseases [110]. As an exception, no correlation between TP53 mutations and EBV status was found in cHL [112].…”

A novel risk score model based on five angiogenesis-related long non-coding RNAs for bladder urothelial carcinoma

“…CD44 polymorphisms probably responding for the susceptibility of BUC were potential for a molecular prognostic marker [ 9 ]. Additionally, the identification of some mutated genes such as FGFR3 [ 10 ], TP53 [ 11 ] and ERCC2 [ 12 , 13 ], led to a resurgent interest in the realm of targeted therapy. An emerging body of studies at the genetic level are discovering more attractive and viable targets.…”

Identification of Prognostic Biomarkers for Bladder Cancer Based on DNA Methylation Profile

“…We found the following conclusions: First, TP53, a well-known tumor suppressor, is unsurprisingly associated with bladder cancer. According to a recent study, RB1 and TP53 co-mutations correlated strongly with genomic biomarkers of response to immunity checkpoint inhibitors in urothelial bladder cancer (Manzano et al, 2021). A meta-analysis provided further evidences that the expression of TP53 mutation was associated with the diagnosis efficiency of advanced bladder cancer.…”