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Mutational processes of tobacco smoking and APOBEC activity generate protein-truncating mutations in cancer genomes.


ABSTRACT: Mutational signatures represent a genomic footprint of endogenous and exogenous mutational processes through tumor evolution. However, their functional impact on the proteome remains incompletely understood. We analyzed the protein-coding impact of single-base substitution (SBS) signatures in 12,341 cancer genomes from 18 cancer types. Stop-gain mutations (SGMs) (i.e., nonsense mutations) were strongly enriched in SBS signatures of tobacco smoking, APOBEC cytidine deaminases, and reactive oxygen species. These mutational processes alter specific trinucleotide contexts and thereby substitute serines and glutamic acids with stop codons. SGMs frequently affect cancer hallmark pathways and tumor suppressors such as TP53, FAT1, and APC. Tobacco-driven SGMs in lung cancer correlate with smoking history and highlight a preventable determinant of these harmful mutations. APOBEC-driven SGMs are enriched in YTCA motifs and associate with APOBEC3A expression. Our study exposes SGM expansion as a genetic mechanism by which endogenous and carcinogenic mutational processes directly contribute to protein loss of function, oncogenesis, and tumor heterogeneity.

SUBMITTER: Adler N 

PROVIDER: S-EPMC10624356 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Mutational processes of tobacco smoking and APOBEC activity generate protein-truncating mutations in cancer genomes.

Adler Nina N   Bahcheli Alexander T AT   Cheng Kevin C L KCL   Al-Zahrani Khalid N KN   Slobodyanyuk Mykhaylo M   Pellegrina Diogo D   Schramek Daniel D   Reimand Jüri J  

Science advances 20231103 44


Mutational signatures represent a genomic footprint of endogenous and exogenous mutational processes through tumor evolution. However, their functional impact on the proteome remains incompletely understood. We analyzed the protein-coding impact of single-base substitution (SBS) signatures in 12,341 cancer genomes from 18 cancer types. Stop-gain mutations (SGMs) (i.e., nonsense mutations) were strongly enriched in SBS signatures of tobacco smoking, APOBEC cytidine deaminases, and reactive oxygen  ...[more]

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