Distinct genomic features across cytolytic subgroups in skin melanoma

Abstract

Background Skin melanoma is a highly immunogenic cancer. The intratumoral immune cytolytic activity (CYT) reflects the ability of cytotoxic T and NK cells to eliminate cancer cells, and is associated with improved patient survival. Despite the enthusiastic clinical results seen in advanced-stage metastatic melanoma patients treated with immune checkpoint inhibitors, a subgroup of them will later relapse and develop acquired resistance. We questioned whether CYT associates with different genomic profiles and thus, patient outcome, in skin melanoma. Methods We explored the TCGA-SKCM dataset and stratified patients to distinct subgroups of cytolytic activity. The tumor immune contexture, somatic mutations and recurrent copy number aberrations were calculated using quanTIseq, MutSigCV and GISTIC2. Chromothriptic events were explored using CTLPScanner and cancer neoepitopes were predicted with antigen garnish. Each tumor's immunophenoscore was calculated using Immunophenogram. Mutational signatures and kataegis were explored using SigProfiler and compared to the known single or doublet base substitution signatures from COSMIC. Results Metastatic skin melanomas had significantly higher CYT levels compared to primary tumors. We assessed enrichment for immune-related gene sets within CYT-high tumors, whereas, CYT-low tumors were enriched for non-immune related gene sets. In addition, distinct mutational and neoantigen loads, primarily composed of C > T transitions, along with specific types of copy number aberrations, characterized each cytolytic subgroup. We found a broader pattern of chromothripsis across CYT-low tumors, where chromosomal regions harboring chromothriptic events, contained a higher number of cancer genes. SBS7a/b, SBS5 and SBS1 were the most prevalent mutational signatures across both cytolytic subgroups, but SBS1 differed significantly between them. SBS7a/b was mutually exclusive with SBS5 and SBS1 in both CYT subgroups. CYT-high patients had markedly higher immunophenoscore, suggesting that they should display a clinical benefit upon treatment with immune checkpoint inhibition therapy, compared to CYT-low patients. Conclusions Overall, our data highlight the existence of distinct genomic features across cytolytic subgroups in skin melanoma, which might affect the patients' relapse rate or their acquisition of resistance to immune checkpoint inhibition therapies.

The comparison of cancer gene mutation frequencies in Chinese and U.S. patient populations

“…However, the proposed etiology of both signatures fell in the category of ultraviolet radiation exposure, which has been associated with DNA replication timing 30 . Additionally, the SBS7a/b signatures were mutually exclusive with the normal aging related mutational signature SBS1/5 31 , 32 . The mutational signatures for PTC_CN and PTC_U.S.…”

Genomic landscape of the immunogenicity regulation in skin melanomas with diverse tumor mutation burden

“…Metastatic tumors on the other hand, were enriched in SBS7b (60,043 mutations; 49.5%) SBS7a (50,904 mutations; 42%), SBS1 (4,124 mutations; 3.4%) and SBS10b (3,823 mutations; 3.2%), followed by a small contribution in SBS5 (1,321 mutations; 1.1%), SBS17b (603 mutations; 0.5%) and SBS17a (357 mutations; 0.3%) ( Figures 4A–C ). Most of these SBSs were previously reported in skin melanoma and their mutational processes are known to cause a high TMB and hypermutation ( 32 , 42 , 66 – 69 ). As regards POLE/POLD1 mutated tumors (SBS10b), they have been shown to have a higher number of neoantigens and infiltrating lymphocytes ( 70 ).…”

“…We calculated IPS scores in TMB high and TMB low tumors (ranging from 0-10) based on the expression of immunomodulators, effector T-cells, effector memory T-cells and immunosuppressors. Their immunophenotypes were visualized using immunophenograms, as previously described ( 41 , 42 ).…”

Immune Cytolytic Activity for Comprehensive Insights of the Immune Landscape in Endometrial Carcinoma

“…It was also worth considering that comprehensive genomic profiling (CGP) with CYT evaluation may exert the additional value for guiding effective immunotherapy or in combination with other therapeutic regiments in EC, particularly refractory EC patients. Finally, it was reasonable to believe that the notion of CYT evaluation through genomic analysis would move beyond the standard stratification of EC in currently clinical practice and provide new evidence to predict T-cell immunity in EC similar to that in melanoma, colon, and lung cancer [19,[33][34], which will be more beneficial for patient management.…”