{"entity":{"id":"paper-alexandrov-tobacco-smoking-mutational-signatures-science-2016","kind":"paper","name":"Mutational signatures associated with tobacco smoking in human cancer","aka":[],"tldr":"Comparing more than five thousand cancers of the types smoking causes showed exactly how tobacco does its damage: in the tissues smoke touches directly it leaves a chemical fingerprint in the DNA, and elsewhere it acts more indirectly.","summary":"Somatic mutations and DNA methylation were analysed in 5,243 cancers of types for which tobacco smoking confers an elevated risk. Smoking is associated with increased mutation burdens of multiple distinct mutational signatures, contributing to different extents in different cancers. One of these, found mainly in cancers derived from tissues directly exposed to tobacco smoke, is attributable to misreplication of DNA damage caused by tobacco carcinogens. Others likely reflect indirect activation of DNA editing by APOBEC cytidine deaminases and of an endogenous clock-like mutational process. Smoking is associated with only limited differences in methylation. The results support the proposition that smoking increases cancer risk by increasing the somatic mutation load, although direct evidence is lacking for some smoking-related cancer types.","asOf":"2026-09-25","links":[{"label":"Alexandrov et al., Science 2016: mutational signatures associated with tobacco smoking in 5,243 cancers","url":"https://doi.org/10.1126/science.aag0299"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/27811275/"}],"tags":[],"related":[],"cancers":["nsclc","sclc"],"sections":[],"technologies":["wes-wgs"],"targets":["kras","tp53"],"drugs":[],"companies":[],"institutions":[],"pathways":["mutagenesis-signatures","chemical-carcinogenesis-receptor-activation","theories-of-cancer"],"terms":["mutational-signature","tmb","kras-mutation-subtypes"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["science"],"dependsOn":[],"notes":[],"journal":"Science","year":2016,"doi":"10.1126/science.aag0299","pmid":"27811275","authors":"Alexandrov LB, Ju YS, Haase K, et al.","paperType":"basic","findings":["Smoking raises mutation burden through several distinct signatures at once.","The carcinogen-adduct signature is confined to directly exposed tissues, lung among them.","APOBEC and clock-like processes are also elevated, indirectly.","Methylation differences associated with smoking are limited."],"whatItMeans":"It supplies the chemistry behind the allele spectrum of lung cancer: the G to T transversion that the tobacco signature generates is why KRAS G12C dominates in lung and G12D dominates in bowel and pancreatic cancer.","caveats":["Cross-sectional genomes, so the causal chain from exposure to mutation to cancer is inferred.","Smoking history is recorded at cohort level with varying quality.","Signature attribution depends on the extraction method used."],"changedPractice":false,"participants":5243},"route":"/key-papers/paper-alexandrov-tobacco-smoking-mutational-signatures-science-2016/","neighbours":{"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"sclc","kind":"cancer","name":"Small-cell lung cancer","route":"/cancers/sclc/"}],"technology":[{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"target":[{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"pathway":[{"id":"chemical-carcinogenesis-receptor-activation","kind":"pathway","name":"Chemical carcinogenesis - receptor activation","route":"/pathways/chemical-carcinogenesis-receptor-activation/"},{"id":"mutagenesis-signatures","kind":"pathway","name":"Mutagenesis & mutational signatures","route":"/pathways/mutagenesis-signatures/"},{"id":"theories-of-cancer","kind":"pathway","name":"Theories of cancer: how the ideas connect","route":"/pathways/theories-of-cancer/"}],"term":[{"id":"kras-mutation-subtypes","kind":"term","name":"KRAS mutation subtypes (G12C, G12D, G12V)","route":"/terms/kras-mutation-subtypes/"},{"id":"mutational-signature","kind":"term","name":"Mutational signature","route":"/terms/mutational-signature/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"}],"journal":[{"id":"science","kind":"journal","name":"Science","route":"/journals/science/"}],"biomarker":[{"id":"kras-g12c","kind":"biomarker","name":"KRAS G12C","route":"/biomarkers/kras-g12c/"},{"id":"kras-g12d","kind":"biomarker","name":"KRAS G12D (and other non-G12C KRAS mutations)","route":"/biomarkers/kras-g12d/"}]}}