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We aimed to assess six DNAm\u2010based smoking predictors in a large sample of middle\u2010aged and older Australians for (i) their accuracy and reliability, and (ii) their association with risk of smoking\u2010related cancers. We used blood DNAm data from the Melbourne Collaborative Cohort Study to calculate six DNAm\u2010based smoking predictors (\n                    <jats:italic>EpiSmokEr<\/jats:italic>\n                    ,\n                    <jats:italic>Elliott\u2010183<\/jats:italic>\n                    ,\n                    <jats:italic>McCartney\u2010233<\/jats:italic>\n                    ,\n                    <jats:italic>DNAmPACKYEARS<\/jats:italic>\n                    ,\n                    <jats:italic>PCPACKYEARS<\/jats:italic>\n                    , and\n                    <jats:italic>mCigarette<\/jats:italic>\n                    ). Accuracy with respect to self\u2010reported smoking pack\u2010years (\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u20092875, median age: 61\u2009years) was assessed using Pearson's correlations, explained variance, and area under the curve (AUC). Reliability was assessed using intraclass correlation coefficients (ICCs) in 364 duplicated samples. Conditional logistic regression was used to assess associations with lung (\n                    <jats:italic>N<\/jats:italic>\n                    <jats:sub>cases<\/jats:sub>\n                    \u2009=\u2009332) and urothelial (\n                    <jats:italic>N<\/jats:italic>\n                    <jats:sub>cases<\/jats:sub>\n                    \u2009=\u2009426) cancer risk in two nested case\u2013control studies. All smoking predictors showed excellent reliability (ICC\u2009&gt;\u20090.9) and ability to distinguish current from never smokers (AUCs: 0.94\u20130.98), explaining 35%\u201350% variance of smoking pack\u2010years. The predictors were positively associated with smoking\u2010related cancer risk, with strongest adjusted associations observed for\n                    <jats:italic>mCigarette<\/jats:italic>\n                    with lung cancer (per SD, rate ratio [RR]\u2009=\u20092.18, 95% CI: 1.57\u20133.02) and for\n                    <jats:italic>PCPACKYEARS<\/jats:italic>\n                    with urothelial cancer (RR\u2009=\u20091.62, 95% CI: 1.27\u20132.07). This translated into prediction gains compared with models solely based on questionnaire\u2010collected smoking variables. In middle\u2010aged and older Australians, DNAm\u2010based smoking predictors showed very good reliability and accuracy in predicting smoking exposure, and strong positive associations with smoking\u2010related cancer risk beyond self\u2010reported smoking information. This highlights their potential utility as an alternative or addition to self\u2010reported smoking information for cancer risk stratification.\n                  <\/jats:p>","DOI":"10.1002\/ijc.70755","type":"journal-article","created":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T12:12:51Z","timestamp":1790424771000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epigenetic Predictors of Smoking: External Validation and Association With Smoking\u2010Related Cancer Risk"],"prefix":"10.1002","author":[{"given":"Xiaoyu","family":"Fan","sequence":"first","affiliation":[{"name":"Precision Medicine, School of Clinical Sciences at Monash Health Monash University  Clayton Victoria Australia"},{"name":"Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health The University of Melbourne  Parkville Victoria 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