Smoking, alcohol consumption, and cancer: A mendelian randomisation study in UK Biobank and international genetic consortia participants

Background Smoking is a well-established cause of lung cancer and there is strong evidence that smoking also increases the risk of several other cancers. Alcohol consumption has been inconsistently associated with cancer risk in observational studies. This mendelian randomisation (MR) study sought to investigate associations in support of a causal relationship between smoking and alcohol consumption and 19 site-specific cancers. Methods and findings We used summary-level data for genetic variants associated with smoking initiation (ever smoked regularly) and alcohol consumption, and the corresponding associations with lung, breast, ovarian, and prostate cancer from genome-wide association studies consortia, including participants of European ancestry. We additionally estimated genetic associations with 19 site-specific cancers among 367,643 individuals of European descent in UK Biobank who were 37 to 73 years of age when recruited from 2006 to 2010. Associations were considered statistically significant at a Bonferroni corrected p-value below 0.0013. Genetic predisposition to smoking initiation was associated with statistically significant higher odds of lung cancer in the International Lung Cancer Consortium (odds ratio [OR] 1.80; 95% confidence interval [CI] 1.59-2.03; p = 2.26 x 10(-21)) and UK Biobank (OR 2.26; 95% CI 1.92-2.65; p = 1.17 x 10(-22)). Additionally, genetic predisposition to smoking was associated with statistically significant higher odds of cancer of the oesophagus (OR 1.83; 95% CI 1.34-2.49; p = 1.31 x 10(-4)), cervix (OR 1.55; 95% CI 1.27-1.88; p = 1.24 x 10(-5)), and bladder (OR 1.40; 95% CI 1.92-2.65; p = 9.40 x 10(-5)) and with statistically nonsignificant higher odds of head and neck (OR 1.40; 95% CI 1.13-1.74; p = 0.002) and stomach cancer (OR 1.46; 95% CI 1.05-2.03; p = 0.024). In contrast, there was an inverse association between genetic predisposition to smoking and prostate cancer in the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium (OR 0.90; 95% CI 0.83-0.98; p = 0.011) and in UK Biobank (OR 0.90; 95% CI 0.80-1.02; p = 0.104), but the associations did not reach statistical significance. We found no statistically significant association between genetically predicted alcohol consumption and overall cancer (n = 75,037 cases; OR 0.95; 95% CI 0.84-1.07; p = 0.376). Genetically predicted alcohol consumption was statistically significantly associated with lung cancer in the International Lung Cancer Consortium (OR 1.94; 95% CI 1.41-2.68; p = 4.68 x 10(-5)) but not in UK Biobank (OR 1.12; 95% CI 0.65-1.93; p = 0.686). There was no statistically significant association between alcohol consumption and any other site-specific cancer. The main limitation of this study is that precision was low in some analyses, particularly for analyses of alcohol consumption and site-specific cancers. Conclusions Our findings support the well-established relationship between smoking and lung cancer and suggest that smoking may also be a risk factor for cancer of the head and neck, oesophagus, stomach, cervix, and bladder. We found no evidence supporting a relationship between alcohol consumption and overall or site-specific cancer risk. Author summary Why was this study done? Tobacco smoking and alcoholic beverage consumption are common addictive behaviours and important risk factors for mortality. Observational evidence has shown that smoking is a risk factor for cancers of the lung, bladder, kidney, gastrointestinal tract, and cervix, but uncertainty persists about the causal role of smoking for the development of other cancers. The causal role of alcohol consumption for site-specific cancers is uncertain, as available evidence originates from observational studies which are susceptible to confounding and reverse causation bias. What did the researchers do and find? Using the mendelian randomisation (MR) design, we found that genetic predisposition to smoking is associated with a statistically significant increased risk of cancer of the lung, oesophagus, cervix, and bladder and with a statistically nonsignificant increased risk of head and neck and stomach cancer at the Bonferroni-corrected significance threshold. Genetically predicted alcohol consumption was statistically significantly positively associated with lung cancer but not with any other site-specific cancer or overall cancer. What do these findings mean? In this study, we observed a relationship between smoking and lung cancer, as well as evidence that smoking may also be a risk factor for cancer of the head and neck, oesophagus, stomach, cervix, and bladder. We found no evidence supporting a relationship between alcohol consumption and overall or site-specific cancer risk.