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Body mass index and breast cancer survival: a Mendelian randomization analysis.

ABSTRACT: Background:There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer. Methods:We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis. Results:BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01-1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89-1.13, P = 0.95). Conclusions:Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases.

SUBMITTER: Guo Q

PROVIDER: S-EPMC5837506 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Body mass index and breast cancer survival: a Mendelian randomization analysis.

Guo Qi Q Burgess Stephen S Turman Constance C Bolla Manjeet K MK Wang Qin Q Lush Michael M Abraham Jean J Aittomäki Kristiina K Andrulis Irene L IL Apicella Carmel C Arndt Volker V Barrdahl Myrto M Benitez Javier J Berg Christine D CD Blomqvist Carl C Bojesen Stig E SE Bonanni Bernardo B Brand Judith S JS Brenner Hermann H Broeks Annegien A Burwinkel Barbara B Caldas Carlos C Campa Daniele D Canzian Federico F Chang-Claude Jenny J Chanock Stephen J SJ Chin Suet-Feung SF Couch Fergus J FJ Cox Angela A Cross Simon S SS Cybulski Cezary C Czene Kamila K Darabi Hatef H Devilee Peter P Diver W Ryan WR Dunning Alison M AM Earl Helena M HM Eccles Diana M DM Ekici Arif B AB Eriksson Mikael M Evans D Gareth DG Fasching Peter A PA Figueroa Jonine J Flesch-Janys Dieter D Flyger Henrik H Gapstur Susan M SM Gaudet Mia M MM Giles Graham G GG Glendon Gord G Grip Mervi M Gronwald Jacek J Haeberle Lothar L Haiman Christopher A CA Hall Per P Hamann Ute U Hankinson Susan S Hartikainen Jaana M JM Hein Alexander A Hiller Louise L Hogervorst Frans B FB Holleczek Bernd B Hooning Maartje J MJ Hoover Robert N RN Humphreys Keith K Hunter David J DJ Hüsing Anika A Jakubowska Anna A Jukkola-Vuorinen Arja A Kaaks Rudolf R Kabisch Maria M Kataja Vesa V Knight Julia A JA Koppert Linetta B LB Kosma Veli-Matti VM Kristensen Vessela N VN Lambrechts Diether D Le Marchand Loic L Li Jingmei J Lindblom Annika A Lindström Sara S Lissowska Jolanta J Lubinski Jan J Machiela Mitchell J MJ Mannermaa Arto A Manoukian Siranoush S Margolin Sara S Marme Federik F Martens John W M JWM McLean Catriona C Menéndez Primitiva P Milne Roger L RL Marie Mulligan Anna A Muranen Taru A TA Nevanlinna Heli H Neven Patrick P Nielsen Sune F SF Nordestgaard Børge G BG Olson Janet E JE Perez Jose I A JIA Peterlongo Paolo P Phillips Kelly-Anne KA Poole Christopher J CJ Pylkäs Katri K Radice Paolo P Rahman Nazneen N Rüdiger Thomas T Rudolph Anja A Sawyer Elinor J EJ Schumacher Fredrick F Seibold Petra P Seynaeve Caroline C Shah Mitul M Smeets Ann A Southey Melissa C MC Tollenaar Rob A E M RAEM Tomlinson Ian I Tsimiklis Helen H Ulmer Hans-Ulrich HU Vachon Celine C van den Ouweland Ans M W AMW Van't Veer Laura J LJ Wildiers Hans H Willett Walter W Winqvist Robert R Zamora M Pilar MP Chenevix-Trench Georgia G Dörk Thilo T Easton Douglas F DF García-Closas Montserrat M Kraft Peter P Hopper John L JL Zheng Wei W Schmidt Marjanka K MK Pharoah Paul D P PDP

International journal of epidemiology 20171201 6

<h4>Background</h4>There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer.<h4>Methods</h4>We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a B ...[more]

PMID: 29232439

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Project description:BackgroundEndometrial cancer is the most common gynaecological cancer in high-income countries. Elevated body mass index (BMI) is an established modifiable risk factor for this condition and is estimated to confer a larger effect on endometrial cancer risk than any other cancer site. However, the molecular mechanisms underpinning this association remain unclear. We used Mendelian randomization (MR) to evaluate the causal role of 14 molecular risk factors (hormonal, metabolic and inflammatory markers) in endometrial cancer risk. We then evaluated and quantified the potential mediating role of these molecular traits in the relationship between BMI and endometrial cancer using multivariable MR.MethodsGenetic instruments to proxy 14 molecular risk factors and BMI were constructed by identifying single-nucleotide polymorphisms (SNPs) reliably associated (P < 5.0 × 10-8) with each respective risk factor in previous genome-wide association studies (GWAS). Summary statistics for the association of these SNPs with overall and subtype-specific endometrial cancer risk (12,906 cases and 108,979 controls) were obtained from a GWAS meta-analysis of the Endometrial Cancer Association Consortium (ECAC), Epidemiology of Endometrial Cancer Consortium (E2C2) and UK Biobank. SNPs were combined into multi-allelic models and odds ratios (ORs) and 95% confidence intervals (95% CIs) were generated using inverse-variance weighted random-effects models. The mediating roles of the molecular risk factors in the relationship between BMI and endometrial cancer were then estimated using multivariable MR.ResultsIn MR analyses, there was strong evidence that BMI (OR per standard deviation (SD) increase 1.88, 95% CI 1.69 to 2.09, P = 3.87 × 10-31), total testosterone (OR per inverse-normal transformed nmol/L increase 1.64, 95% CI 1.43 to 1.88, P = 1.71 × 10-12), bioavailable testosterone (OR per natural log transformed nmol/L increase: 1.46, 95% CI 1.29 to 1.65, P = 3.48 × 10-9), fasting insulin (OR per natural log transformed pmol/L increase: 3.93, 95% CI 2.29 to 6.74, P = 7.18 × 10-7) and sex hormone-binding globulin (SHBG, OR per inverse-normal transformed nmol/L increase 0.71, 95% CI 0.59 to 0.85, P = 2.07 × 10-4) had a causal effect on endometrial cancer risk. Additionally, there was suggestive evidence that total serum cholesterol (OR per mg/dL increase 0.90, 95% CI 0.81 to 1.00, P = 4.01 × 10-2) had an effect on endometrial cancer risk. In mediation analysis, we found evidence for a mediating role of fasting insulin (19% total effect mediated, 95% CI 5 to 34%, P = 9.17 × 10-3), bioavailable testosterone (15% mediated, 95% CI 10 to 20%, P = 1.43 × 10-8) and SHBG (7% mediated, 95% CI 1 to 12%, P = 1.81 × 10-2) in the relationship between BMI and endometrial cancer risk.ConclusionsOur comprehensive MR analysis provides insight into potential causal mechanisms linking BMI with endometrial cancer risk and suggests targeting of insulinemic and hormonal traits as a potential strategy for the prevention of endometrial cancer.

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Body mass index and breast cancer survival: a Mendelian randomization analysis.

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Body mass index and breast cancer survival: a Mendelian randomization analysis.

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