Abstract 1319: Distinct pancancer mutational signatures are determined by APOBEC/ADAR aberrations

Abstract

Abstract Background: Known endogenous mutators include certain APOBEC family member, whose mRNA levels have been implicated in various cancers. Other important nucleic acid deaminases include ADAR family of proteins, with some recent evidence supporting their potential mutator activity. Some external mutators have also been reported to act through endogenous ones. Although the ADAR and particularly APOBEC mutations are infrequent among cancer genomes, their potential contributions in cancer mutagenesis might not be underestimated. Methods: We assessed 10,294 TCGA samples from 32 cancer types for mutations among fourteen APOBEC/ADAR family members. The relative contributions of COSMIC mutational signatures were determined among each of 9,294 exomes (32 cancer types) and 828 genomes (21 cancer types). Multivariate analyses identified the relative impacts of APOBEC/ADAR mutations and mRNA levels as well as DNA repair/replication defects, as determined by mutations in KEGG pathway genes, on mutational signatures across exomes/genomes, in addition to their means across cancer types. Results: Analysis of exome signatures across both cancer samples and cancer types identified SBS2 and SBS13 highly correlated with A3B mRNA level, as expected. Age-related SBS1 was highly determined by APOBEC1 (A1) mRNA level, so did 5FU-related SBS17b moderately. UV-related SBS7a,b were highly determined by ADARB1 mRNA levels, and both tobacco-related SBS29 and homologous recombination (HR)-related SBS3 were found to be moderately determined by ADAR mRNA levels. Both alkylator-related SBS11 and unknown SBS37 were seen to be highly determined by ADARB2 mRNA levels, so did unknown SBS39 moderately. Replication-related ID1 was found to be highly determined HR mutations. Moreover, analysis of genome signatures across both cancer samples and cancer types identified SBS2 and SBS13 highly correlated with A3B mRNA level, and UV-related SBS7a-d, SBS38, ID13 and DBS1 were highly determined by ADARB1 mRNA level. Tobacco-related SBS4 and unknown ID4 were highly determined by ADARB2 mRNA level. POLH-related SBS9, replication-related ID2, unknown SBS34, and the so-called artefact SBS56 were highly determined by AICDA mRNA level. Finally, ROS-related SBS18, replication-related ID2, MMR-related ID7 and DBS7, and unknown ID14 were highly determined by A1 mRNA level, so did 5FU-related SBS17a,b, unknown DBS8, and the so-called artefact SBS45 moderately. Essentially all of ADARB1 impact on UV-related signatures seems to be dependent on UV itself. Conclusions: These results potentially implicate certain APOBEC/ADAR mutations and mRNA levels in distinct mutational signatures, mandating further functional analyses. They might reflect the gain/ loss of function impacts of various mutations and/or oligomer forms of both families. While similar exome/genome findings can be corroborating, some differential findings might indicate truly differential mutagenic mechanisms in coding vs. noncoding genome. Citation Format: Ahmadreza Niavarani, Asieh Shahrabi Farahani, Maryam Sharafkhah, Ludmil B. Alexandrov, Reza Malekzadeh. Distinct pancancer mutational signatures are determined by APOBEC/ADAR aberrations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1319.