Dataset Information

Mendelian randomisation study of smoking exposure in relation to breast cancer risk.

ABSTRACT:

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^-2), 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.

SUBMITTER: Park HA

PROVIDER: S-EPMC8505411 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

Mendelian randomisation study of smoking exposure in relation to breast cancer risk.

Park Hanla A HA Neumeyer Sonja S Michailidou Kyriaki K Bolla Manjeet K MK Wang Qin Q Dennis Joe J Ahearn Thomas U TU Andrulis Irene L IL Anton-Culver Hoda H Antonenkova Natalia N NN Arndt Volker V Aronson Kristan J KJ Augustinsson Annelie A Baten Adinda A Beane Freeman Laura E LE Becher Heiko H Beckmann Matthias W MW Behrens Sabine S Benitez Javier J Bermisheva Marina M Bogdanova Natalia V NV Bojesen Stig E SE Brauch Hiltrud H Brenner Hermann H Brucker Sara Y SY Burwinkel Barbara B Campa Daniele D Canzian Federico F Castelao Jose E JE Chanock Stephen J SJ Chenevix-Trench Georgia G Clarke Christine L CL Conroy Don M DM Couch Fergus J FJ Cox Angela A Cross Simon S SS Czene Kamila K Daly Mary B MB Devilee Peter P Dörk Thilo T Dos-Santos-Silva Isabel I Dwek Miriam M Eccles Diana M DM Eliassen A Heather AH Engel Christoph C Eriksson Mikael M Evans D Gareth DG Fasching Peter A PA Flyger Henrik H Fritschi Lin L García-Closas Montserrat M García-Sáenz José A JA Gaudet Mia M MM Giles Graham G GG Glendon Gord G Goldberg Mark S MS Goldgar David E DE González-Neira Anna A Grip Mervi M Guénel Pascal P Hahnen Eric E Haiman Christopher A CA Håkansson Niclas N Hall Per P Hamann Ute U Han Sileny S Harkness Elaine F EF Hart Steven N SN He Wei W Heemskerk-Gerritsen Bernadette A M BAM Hopper John L JL Hunter David J DJ Jager Agnes A Jakubowska Anna A John Esther M EM Jung Audrey A Kaaks Rudolf R Kapoor Pooja Middha PM Keeman Renske R Khusnutdinova Elza E Kitahara Cari M CM Koppert Linetta B LB Koutros Stella S Kristensen Vessela N VN Kurian Allison W AW Lacey James J Lambrechts Diether D Le Marchand Loic L Lo Wing-Yee WY Lubiński Jan J Mannermaa Arto A Manoochehri Mehdi M Margolin Sara S Martinez Maria Elena ME Mavroudis Dimitrios D Meindl Alfons A Menon Usha U Milne Roger L RL Muranen Taru A TA Nevanlinna Heli H Newman William G WG Nordestgaard Børge G BG Offit Kenneth K Olshan Andrew F AF Olsson Håkan H Park-Simon Tjoung-Won TW Peterlongo Paolo P Peto Julian J Plaseska-Karanfilska Dijana D Presneau Nadege N Radice Paolo P Rennert Gad G Rennert Hedy S HS Romero Atocha A Saloustros Emmanouil E Sawyer Elinor J EJ Schmidt Marjanka K MK Schmutzler Rita K RK Schoemaker Minouk J MJ Schwentner Lukas L Scott Christopher C Shah Mitul M Shu Xiao-Ou XO Simard Jacques J Smeets Ann A Southey Melissa C MC Spinelli John J JJ Stevens Victoria V Swerdlow Anthony J AJ Tamimi Rulla M RM Tapper William J WJ Taylor Jack A JA Terry Mary Beth MB Tomlinson Ian I Troester Melissa A MA Truong Thérèse T Vachon Celine M CM van Veen Elke M EM Vijai Joseph J Wang Sophia S Wendt Camilla C Winqvist Robert R Wolk Alicja A Ziogas Argyrios A Dunning Alison M AM Pharoah Paul D P PDP Easton Douglas F DF Zheng Wei W Kraft Peter P Chang-Claude Jenny J

British journal of cancer 20210802 8

<h4>Background</h4>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.<h4>Methods</h4>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 stu ...[more]

PMID: 34341517

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Project description:ObjectivesPhysical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.MethodsWe performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.ResultsGreater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).ConclusionOur study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.

Project description:BackgroundStudies on the relationship between personal history of irradiation and breast cancer have been reported for a long time. Still, epidemiological studies have not been conclusive, and the causal relationship is unclear. To address this issue, we employed Mendelian randomisation (MR) analysis to examine the association between individual radiation exposure history and breast cancer.MethodsWe used a series of quality control methods to select single nucleotide polymorphism (SNP) closely related to exposure. Meanwhile, several analysis methods were used to analyse the sample data to make the conclusion more reliable. To evaluate the horizontal pleiotropy, heterogeneity and stability of SNPs for breast cancer, the MR-Egger intercept test, Cochran's Q test and 'leave one' sensitivity analysis were used. Finally, the outlier variation determined by the Mendelian Randomisation Pleiotropy RESidual Sum and Outlier test is gradually eliminated to reduce the influence of heterogeneity and horizontal pleiotropy.ResultsAfter implementing rigorous quality control procedures, we carefully chose 102 qualified instrumental variables closely associated with the selected exposure for sensitivity analysis. This was conducted to evaluate the heterogeneity, level multiplicity, and stability of SNPs in the context of personal radiation history and its correlation with breast cancer. The results of the inverse variance weighted method analysis revealed a positive correlation between personal radiation and a heightened risk of breast cancer (odds ratio (OR) = 1.52; 95% confidence interval (CI) = 1.30-1.77). We also validated on another data set; the results were similar (OR = 1.51; 95% CI = 1.27-1.81). Furthermore, the findings from the sensitivity analysis were consistent. At the genetic level, our research demonstrated that personal radiation exposure is associated with an elevated risk of breast cancer.ConclusionsUsing genetic data provides evidence and strengthens the causal link that personal radiation causes breast cancer.

Project description:BackgroundObservational studies have investigated the association of risk factors with breast cancer prognosis. However, the results have been conflicting and it has been challenging to establish causality due to potential residual confounding. Using a Mendelian randomisation (MR) approach, we aimed to examine the potential causal association between breast cancer-specific survival and nine established risk factors for breast cancer: alcohol consumption, body mass index, height, physical activity, mammographic density, age at menarche or menopause, smoking, and type 2 diabetes mellitus (T2DM).MethodsWe conducted a two-sample MR analysis on data from the Breast Cancer Association Consortium (BCAC) and risk factor summary estimates from the GWAS Catalog. The BCAC data included 86,627 female patients of European ancestry with 7054 breast cancer-specific deaths during 15 years of follow-up. Of these, 59,378 were estrogen receptor (ER)-positive and 13,692 were ER-negative breast cancer patients. For the significant association, we used sensitivity analyses and a multivariable MR model. All risk factor associations were also examined in a model adjusted by other prognostic factors.ResultsIncreased genetic liability to T2DM was significantly associated with worse breast cancer-specific survival (hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.03-1.17, P value [P] = 0.003). There were no significant associations after multiple testing correction for any of the risk factors in the ER-status subtypes. For the reported significant association with T2DM, the sensitivity analyses did not show evidence for violation of the MR assumptions nor that the association was due to increased BMI. The association remained significant when adjusting by other prognostic factors.ConclusionsThis extensive MR analysis suggests that T2DM may be causally associated with worse breast cancer-specific survival and therefore that treating T2DM may improve prognosis.

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Dataset Information

Mendelian randomisation study of smoking exposure in relation to breast cancer risk.

Background

Methods

Results

Conclusion

Publications

Mendelian randomisation study of smoking exposure in relation to breast cancer risk.

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