Mendelian Randomisation Study of Smoking Exposure in Relation to Breast Cancer Risk

Background: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk.

Methods: We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy.

Results: Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect.

Conclusion: Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.

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References

Bray F, Ferlay J, Soerjomataram I, Siegel R, Torre L, Jemal A . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6):394-424. DOI: 10.3322/caac.21492. View

Hecht S . Tobacco smoke carcinogens and breast cancer. Environ Mol Mutagen. 2002; 39(2-3):119-26. DOI: 10.1002/em.10071. View

PETRAKIS N, Gruenke L, Beelen T, Castagnoli Jr N, Craig J . Nicotine in breast fluid of nonlactating women. Science. 1978; 199(4326):303-5. DOI: 10.1126/science.619458. View

PETRAKIS N, Maack C, Lee R, Lyon M . Mutagenic activity in nipple aspirates of human breast fluid. Cancer Res. 1980; 40(1):188-9. View

Conway K, Edmiston S, Cui L, Drouin S, Pang J, He M . Prevalence and spectrum of p53 mutations associated with smoking in breast cancer. Cancer Res. 2002; 62(7):1987-95. View

Li D, Zhang W, Sahin A, Hittelman W . DNA adducts in normal tissue adjacent to breast cancer: a review. Cancer Detect Prev. 1999; 23(6):454-62. DOI: 10.1046/j.1525-1500.1999.99059.x. View

Rundle A, Tang D, Hibshoosh H, Estabrook A, Schnabel F, Cao W . The relationship between genetic damage from polycyclic aromatic hydrocarbons in breast tissue and breast cancer. Carcinogenesis. 2000; 21(7):1281-9. View

Warren G, Alberg A, Kraft A, Cummings K . The 2014 Surgeon General's report: "The health consequences of smoking--50 years of progress": a paradigm shift in cancer care. Cancer. 2014; 120(13):1914-6. PMC: 5928784. DOI: 10.1002/cncr.28695. View

Band P, Le N, Fang R, Deschamps M . Carcinogenic and endocrine disrupting effects of cigarette smoke and risk of breast cancer. Lancet. 2002; 360(9339):1044-9. DOI: 10.1016/S0140-6736(02)11140-8. View

10.

Clemons M, Goss P . Estrogen and the risk of breast cancer. N Engl J Med. 2001; 344(4):276-85. DOI: 10.1056/NEJM200101253440407. View

11.

Gaudet M, Carter B, Brinton L, Falk R, Gram I, Luo J . Pooled analysis of active cigarette smoking and invasive breast cancer risk in 14 cohort studies. Int J Epidemiol. 2016; 46(3):881-893. PMC: 5837778. DOI: 10.1093/ije/dyw288. View

12.

Davey Smith G, Ebrahim S . 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease?. Int J Epidemiol. 2003; 32(1):1-22. DOI: 10.1093/ije/dyg070. View

13.

Evans D, Davey Smith G . Mendelian Randomization: New Applications in the Coming Age of Hypothesis-Free Causality. Annu Rev Genomics Hum Genet. 2015; 16:327-50. DOI: 10.1146/annurev-genom-090314-050016. View

14.

Burgess S, Bowden J, Fall T, Ingelsson E, Thompson S . Sensitivity Analyses for Robust Causal Inference from Mendelian Randomization Analyses with Multiple Genetic Variants. Epidemiology. 2016; 28(1):30-42. PMC: 5133381. DOI: 10.1097/EDE.0000000000000559. View

15.

Michailidou K, Lindstrom S, Dennis J, Beesley J, Hui S, Kar S . Association analysis identifies 65 new breast cancer risk loci. Nature. 2017; 551(7678):92-94. PMC: 5798588. DOI: 10.1038/nature24284. View

16.

Michailidou K, Hall P, Gonzalez-Neira A, Ghoussaini M, Dennis J, Milne R . Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet. 2013; 45(4):353-61, 361e1-2. PMC: 3771688. DOI: 10.1038/ng.2563. View

17.

Howie B, Fuchsberger C, Stephens M, Marchini J, Abecasis G . Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat Genet. 2012; 44(8):955-9. PMC: 3696580. DOI: 10.1038/ng.2354. View

18.

Wootton R, Richmond R, Stuijfzand B, Lawn R, Sallis H, Taylor G . Evidence for causal effects of lifetime smoking on risk for depression and schizophrenia: a Mendelian randomisation study. Psychol Med. 2019; 50(14):2435-2443. PMC: 7610182. DOI: 10.1017/S0033291719002678. View

19.

Liu M, Jiang Y, Wedow R, Li Y, Brazel D, Chen F . Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat Genet. 2019; 51(2):237-244. PMC: 6358542. DOI: 10.1038/s41588-018-0307-5. View

20.

Lu Z, Zhu M, Marley J, Bi K, Wang K, Zhai M . The combined action of monocytic myeloid-derived suppressor cells and mucosal-associated invariant T cells promotes the progression of cervical cancer. Int J Cancer. 2020; 148(6):1499-1507. DOI: 10.1002/ijc.33411. View