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. 2021 Apr 20;21(1):432.
doi: 10.1186/s12885-021-08078-y.

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

Ramon Gonzalez Manzano  1 , Ana Catalan-Latorre  2 , Antonio Brugarolas  3
Affiliations

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

Ramon Gonzalez Manzano et al. BMC 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.

Keywords: Bladder; Cancer; Co-mutation; Immunity checkpoint inhibitor; RB1; Signature; TP53; Urothelial.

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Conflict of interest statement

The authors declare that they have no competing interests

Figures

Fig. 1
Fig. 1
DNA somatic signatures obtained from full exome data in a DWT and b RB1&TP53. CS refers to the value of Cosine-Similarity
Fig. 2
Fig. 2
Most recurrent mutations obtained from full exome data in a DWT and b RB1&TP53, please note that the figure does not include the RB1 HD present in several of the samples but not plotted. Hence, all samples shown in B) are co-altered and have RB1 alterations
Fig. 3
Fig. 3
Kaplan-Meier curves of the IMVigor 210 study, using the Tumor Microenvironment Metascore (TMM) as a continuous variable split by quartiles
Fig. 4
Fig. 4
Correlation between the clinical response to atezolizumab in the IMVigor 210 study according to RECIST v1.1 criteria and a the Tumor Mutational Burden (TMB) and b the TMM. CR: Complete Response; PR: Partial Response; SD: Stable Disease; PD: Progressive disease. ** P value < 0.01; *** P value < 0.001, Wilcoxon rank sum test, two-sided
Fig. 5
Fig. 5
Kaplan Meier curves using the TMM as a continuous variable split by A) the median B) the first quartile in the urothelial bladder cancer TCGA dataset
Fig. 6
Fig. 6
Subset of the IMVigor 210 study (n = 274) classified according to the latest consensus molecular subtype classification, separated by a Mutational status regarding RB1 and TP53 alterations and b binary response to atezolizumab: Responders (CR + PR) and Non-responders (SD + PD)). The y-axis in this figure refers to the number of patients
Fig. 7
Fig. 7
Boxplots showing the differences in a TMB and b TMM, between the different consensus molecular subtypes. * P value < 0.05; ** P value < 0.01, Wilcoxon rank sum test, two-sided
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