Physical activity and risks of breast and colorectal cancer: a Mendelian randomisation analysis

Nikos Papadimitriou ,Andrea Gsur ,Vı́ctor Moreno ,Bas Bueno‐De‐Mesquita ,Brigid M Lynch ,Bethany Van Guelpen ,Demetrius Albanês ,Jenny Chang‐Claude ,Temitope O Keku ,Konstantinos K Tsilidis ,Tim Robinson ,Michael Hoffmeister ,Gad Rennert ,Tabitha A Harrison ,Loı̈c Le Marchand ,John L Hopper ,Anna H Wu ,Christopher I Li ,Hermann Brenner ,Stephen N Thibodeau ,Harald Hampel ,Antonia Trichopoulou ,Evelyn M Monninkhof ,Elizabeth A Platz ,Mark A Jenkins ,Jane C Figueiredo ,Gianluca Severi ,Graham G Giles ,María José Sánchez ,Fränzel J.b Van Duijnhoven ,Martha L Slattery ,Annika Lindblom ,John D Potter ,Vittorio Perduca ,Elio Riboli ,Noralane M Lindor ,Sonja I Berndt ,Pavel Vodička ,Ruth C Travis ,Mingyang Song ,Stephen B Gruber ,Polly A Newcomb ,Kenneth Offit ,Jochen Hampe ,Richard M Martin ,Anne M May ,Jeroen R Huyghe ,Emily White ,Krasimira Aleksandrova ,Andrew T Chan ,Edward Giovannucci ,Sophia Harlid ,Nabila Kazmi ,Steven Gallinger ,Robert E Schoen ,Cornelia M Ulrich ,Paul D.p Pharoah ,Li Hsu ,Giovanna Masala ,Tilman Kühn ,Lorena Moreno ,D Timothy Bishop ,Sabina Sieri ,Daniel D Buchanan ,Sergi Castellví–Bel ,Merete Ellingjord-Dale ,Carlo La Vecchia ,Stephanie L Schmit ,Peter T Campbell ,Michael O Woods ,Marc J Gunter ,Roger L Milne ,Niki Dimou ,José María Huerta ,Catherine M Tangen ,Sarah J Lewis ,Alicja Wolk ,Li Li ,Sanford D Markowitz ,Barbara L Banbury ,Ulrike Peters ,Neil Murphy

doi:10.1038/s41467-020-14389-8

Abstract

Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value = 0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value = 0.01). We found similar magnitude inverse associations for estrogen positive (ER+ve) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers.

Highlights

Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; it is unknown if these associations are causal or confounded
We estimated that a 1 standard deviation (SD) (8.14 milligravities) increment in the genetically predicted levels of accelerometer-measured physical activity was associated with a 49% lower risk of breast cancer for the instrument using the 5 genome-wide-significant Single nucleotide polymorphisms (SNPs) instrument (Table 1), and a 41% lower risk for the extended 10 SNP instrument (OR: 0.59, 95% CI: 0.42 to 0.84, P-value = 0.003, Q-value = 0.012)
An inverse association was only found for estrogen receptor positive breast cancer (ER+ve) (5 SNP instrument, OR: 0.45, 95% CI: 0.20 to 1.01, P-value = 0.054, Q-value = 0.077; extended 10 SNP instrument, OR: 0.53, 95% CI: 0.35 to 0.82, P-value = 0.004, Q-value = 0.004), and not estrogen receptor negative (ER-ve) breast cancer (Table 1); this heterogeneity by subtype was not statistically different (I2 = 16%; P-heterogeneity by subtype = 0.27)

Summary

Introduction

Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; it is unknown if these associations are causal or confounded. More objective methods to measure physical activity, such as accelerometry, have seldom been used in large-scale epidemiological studies, with the UK Biobank being a recent exception in which ~100,000 participants wore a wrist accelerometer for 7-days to measure total activity levels[8] Epidemiological analyses of these data will provide important new evidence on the link between physical activity and cancer, but these analyses remain vulnerable to other biases of observational epidemiology such as residual confounding (e.g. low physical activity levels may be correlated with other unfavourable health behaviours) and reverse causality (e.g. preclinical cancer symptoms may have resulted in low physical activity levels). We used a two-sample MR framework to examine potential causal associations between objective accelerometer-measured physical activity and risks of breast and colorectal cancer using genetic variants associated with accelerometer-measured physical activity identified from two recent genome-wide association studies (GWAS)[11,12]. We examined the associations of these genetic variants with risks of breast cancer[13] and colorectal cancer[14]

Methods

Results

Conclusion