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

Adler, Nina; Bahcheli, Alexander T.; Cheng, Kevin C. L.; Al-Zahrani, Khalid N.; Slobodyanyuk, Mykhaylo; Pellegrina, Diogo; Schramek, Daniel; Reimand, Jüri

doi:10.1126/sciadv.adh3083

Cited by 2 publications

(2 citation statements)

References 66 publications

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“…Carcinogens in cigarette smoke can directly mutate tumor suppressor genes and oncogenes, while cigarette smoke-induced inflammation creates a tumor-promoting microenvironment in the lungs. The relationship is dosedependent, with lung cancer risk and mortality higher with greater smoking intensity and pack-years (Adler et al 2023;Voskarides and Giannopoulou 2023;Feng et al 2006). Smoking cessation decreases risk, but former smokers remain at elevated lifetime risk compared to never smokers.…”

Section: Respiratory Effectsmentioning

confidence: 99%

Oxidative stress and inflammation: elucidating mechanisms of smoking-attributable pathology for therapeutic targeting

Addissouky,

El Sayed,

Ali

et al. 2024

Bull Natl Res Cent

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Background Tobacco smoking remains a major preventable cause of disease and death worldwide. Combustible cigarettes release thousands of chemicals that can initiate inflammatory pathways leading to smoking-related illness. This review aims to synthesize current scientific knowledge on mechanisms of smoking-induced disease, epidemiological trends, and clinical strategies from recent literature. Main body of the abstract At the cellular level, cigarette smoke triggers oxidative stress through reactive oxygen species (ROS), causing DNA damage. This provokes inflammatory signaling cascades mediated by damage-associated molecular patterns (DAMPs), receptors like RAGE and TLRs, and downstream cytokines. Smoking also disrupts apoptosis and autophagy. In the lungs, oxidative stress and inflammation from smoking play central roles in COPD pathogenesis. Smoking-induced oxidative DNA damage, chronic inflammation, and impaired immunity combine to promote lung carcinogenesis. For cardiovascular disease, smoking triggers endothelial dysfunction, platelet activation, and atherogenesis through oxidized LDL and effects on nitric oxide and adhesion molecules. Short conclusion Given the unequivocal evidence of health risks, smoking cessation is critical to reducing preventable death and disability. Both counseling and pharmacotherapy have proven efficacy for quitting, but efficacy remains limited long-term. Emerging nicotine products like e-cigarettes have unknown impacts on cessation and population health. Comprehensive efforts encompassing prevention, screening, treatment innovation, harm reduction, and policy reform focused on curbing smoking-attributable morbidity and mortality are warranted.

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Section: Respiratory Effectsmentioning

confidence: 99%

Oxidative stress and inflammation: elucidating mechanisms of smoking-attributable pathology for therapeutic targeting

Addissouky,

El Sayed,

Ali

et al. 2024

Bull Natl Res Cent

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“…The high-score group was also characterized by SBS4 (exposure to tobacco [smoking] mutagens). A recent genomic study revealed that tobacco-driven SBS4 and APOBEC signature SBS13 were enriched in stop-gain mutations (SGMs) in various cancer types [ 54 ]. C > G and C > A mutations are common to SBS13, while C > T mutations are common to SBS2.…”

Section: Discussionmentioning

confidence: 99%

Mutational variant allele frequency profile as a biomarker of response to immune checkpoint blockade in non-small cell lung Cancer

Gao,

Lou,

et al. 2024

J Transl Med

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Introduction Identifying new biomarkers for predicting immune checkpoint inhibitors (ICIs) response in non-small cell lung cancer (NSCLC) is crucial. We aimed to assess the variant allele frequency (VAF)-related profile as a novel biomarker for NSCLC personalized therapy. Methods We utilized genomic data of 915 NSCLC patients via cBioPortal and a local cohort of 23 patients for model construction and mutational analysis. Genomic, transcriptomic data from 952 TCGA NSCLC patients, and immunofluorescence (IF) assessment with the local cohort supported mechanism analysis. Results Utilizing the random forest algorithm, a 15-gene VAF-related model was established, differentiating patients with durable clinical benefit (DCB) from no durable benefit (NDB). The model demonstrated robust performance, with ROC-AUC values of 0.905, 0.737, and 0.711 across training (n = 313), internal validation (n = 133), and external validation (n = 157) cohorts. Stratification by the model into high- and low-score groups correlated significantly with both progression-free survival (PFS) (training: P < 0.0001, internal validation: P < 0.0001, external validation: P = 0.0066) and overall survival (OS) (n = 341) (P < 0.0001). Notably, the stratification system was independent of PD-L1 (P < 0.0001) and TMB (P < 0.0001). High-score patients exhibited an increased DCB ratio and longer PFS across both PD-L1 and TMB subgroups. Additionally, the high-score group appeared influenced by tobacco exposure, with activated DNA damage response pathways. Whereas, immune/inflammation-related pathways were enriched in the low-score group. Tumor immune microenvironment analyses revealed higher proportions of exhausted/effector memory CD8 + T cells in the high-score group. Conclusions The mutational VAF profile is a promising biomarker for ICI therapy in NSCLC, with enhanced therapeutic stratification and management as a supplement to PD-L1 or TMB.

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

Cited by 2 publications

References 66 publications

Oxidative stress and inflammation: elucidating mechanisms of smoking-attributable pathology for therapeutic targeting

Oxidative stress and inflammation: elucidating mechanisms of smoking-attributable pathology for therapeutic targeting

Mutational variant allele frequency profile as a biomarker of response to immune checkpoint blockade in non-small cell lung Cancer

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