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APOBEC Mutagenesis in Cancer Development and Susceptibility.

ABSTRACT: APOBEC cytosine deaminases are prominent mutators in cancer, mediating mutations in over 50% of cancers. APOBEC mutagenesis has been linked to tumor heterogeneity, persistent cell evolution, and therapy responses. While emerging evidence supports the impact of APOBEC mutagenesis on cancer progression, the understanding of its contribution to cancer susceptibility and malignant transformation is limited. We examine the existing evidence for the role of APOBEC mutagenesis in carcinogenesis on the basis of the reported associations between germline polymorphisms in genes encoding APOBEC enzymes and cancer risk, insights into APOBEC activities from sequencing efforts of both malignant and non-malignant human tissues, and in vivo studies. We discuss key knowledge gaps and highlight possible ways to gain a deeper understanding of the contribution of APOBEC mutagenesis to cancer development.

SUBMITTER: Dananberg A

PROVIDER: S-EPMC10814203 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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APOBEC Mutagenesis in Cancer Development and Susceptibility.

Dananberg Alexandra A Striepen Josefine J Rozowsky Jacob S JS Petljak Mia M

Cancers 20240115 2

APOBEC cytosine deaminases are prominent mutators in cancer, mediating mutations in over 50% of cancers. APOBEC mutagenesis has been linked to tumor heterogeneity, persistent cell evolution, and therapy responses. While emerging evidence supports the impact of APOBEC mutagenesis on cancer progression, the understanding of its contribution to cancer susceptibility and malignant transformation is limited. We examine the existing evidence for the role of APOBEC mutagenesis in carcinogenesis on the ...[more]

PMID: 38254863

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Project description:Mutations in somatic cells are inflicted by both extrinsic and intrinsic sources and contribute over time to cancer. Tobacco smoke contains chemical carcinogens that have been causatively implicated with cancers of the lung and head & neck1,2. APOBEC family DNA cytosine deaminases have emerged as endogenous sources of mutation in cancer, with hallmark mutational signatures (SBS2/SBS13) that often co-occur in tumors of tobacco smokers with an equally diagnostic mutational signature (SBS4)3,4. Here we challenge the dogma that mutational processes are thought to occur independently and with additive impact by showing that 4-nitroquinoline 1-oxide (NQO), a model carcinogen for tobacco exposure, sensitizes cells to APOBEC3B (A3B) mutagenesis and leads to synergistic increases in both SBS2 mutation loads and oral carcinomas in vivo. NQO-exposed/A3B-expressing animals exhibit twice as many head & neck lesions as carcinogen-exposed wildtype animals. This increase in carcinogenesis is accompanied by a synergistic increase in mutations from APOBEC signature SBS2, but not from NQO signature SBS4. Interestingly, a large proportion of A3B-catalyzed SBS2 mutations occurs as strand-coordinated pairs within 32 nucleotides of each other in transcribed regions, suggesting a mechanism in which removal of NQO-DNA adducts by nucleotide excision repair exposes short single-stranded DNA tracts to enzymatic deamination. These highly enriched pairs of APOBEC signature mutations are termed didyma (Greek for twins) and are mechanistically distinct from other types of clustered mutation (omikli and kataegis). Computational analyses of lung and head & neck tumor genomes show that both APOBEC mutagenesis and didyma are elevated in cancers from smokers compared to non-smokers. APOBEC signature mutations and didyma are also elevated in normal lung tissues in smokers prior to cancer initiation. Collectively, these results indicate that DNA adducting mutagens in tobacco smoke can amplify DNA damage and mutagenesis by endogenous APOBEC enzymes and, more broadly, suggest that mutational mechanisms can interact synergistically in both cancer initiation and promotion.

Project description:BackgroundStudies of targeted therapy resistance in lung cancer have primarily focused on single-gene alterations. Based on prior work implicating apolipoprotein b mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) mutagenesis in histological transformation of epidermal growth factor receptor (EGFR)-mutant lung cancers, we hypothesized that mutational signature analysis may help elucidate acquired resistance to targeted therapies.Patients and methodsAPOBEC mutational signatures derived from an Food and Drug Administration-cleared multigene panel [Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)] using the Signature Multivariate Analysis (SigMA) algorithm were validated against the gold standard of mutational signatures derived from whole-exome sequencing. Mutational signatures were decomposed in 3276 unique lung adenocarcinomas (LUADs), including 93 paired osimertinib-naïve and -resistant EGFR-mutant tumors. Associations between APOBEC and mechanisms of resistance to osimertinib were investigated. Whole-genome sequencing was carried out on available EGFR-mutant lung cancer samples (10 paired, 17 unpaired) to investigate large-scale genomic alterations potentially contributing to osimertinib resistance.ResultsAPOBEC mutational signatures were more frequent in receptor tyrosine kinase (RTK)-driven lung cancers (EGFR, ALK, RET, and ROS1; 25%) compared to LUADs at large (20%, P < 0.001); across all subtypes, APOBEC mutational signatures were enriched in subclonal mutations (P < 0.001). In EGFR-mutant lung cancers, osimertinib-resistant samples more frequently displayed an APOBEC-dominant mutational signature compared to osimertinib-naïve samples (28% versus 14%, P = 0.03). Specifically, mutations detected in osimertinib-resistant tumors but not in pre-treatment samples significantly more frequently displayed an APOBEC-dominant mutational signature (44% versus 23%, P < 0.001). EGFR-mutant samples with APOBEC-dominant signatures had enrichment of large-scale genomic rearrangements (P = 0.01) and kataegis (P = 0.03) in areas of APOBEC mutagenesis.ConclusionsAPOBEC mutational signatures are frequent in RTK-driven LUADs and increase under the selective pressure of osimertinib in EGFR-mutant lung cancer. APOBEC mutational signature enrichment in subclonal mutations, private mutations acquired after osimertinib treatment, and areas of large-scale genomic rearrangements highlights a potentially fundamental role for APOBEC mutagenesis in the development of resistance to targeted therapies, which may be potentially exploited to overcome such resistance.

Dataset Information

APOBEC Mutagenesis in Cancer Development and Susceptibility.

Publications

APOBEC Mutagenesis in Cancer Development and Susceptibility.

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