The Role of Mendelian Randomization Studies in Deciphering the Effect of Obesity on Cancer

Abstract

Associations of obesity have been established for at least 11 cancer sites in observational studies, though some questions remain as to causality, strength of associations, and timing of associations throughout the life course. In recent years, Mendelian randomization (MR) has provided complementary information to traditional approaches, but the validity requires that the genetic instrumental variables be causally related to cancers only mediated by the exposure. We summarize and evaluate existing evidence from MR studies in comparison with conventional observational studies to provide insights into the complex relationship between obesity and multiple cancers. MR studies further establish the causality of adult obesity with esophageal adenocarcinoma, cancers of the colorectum, endometrium, ovary, kidney, and pancreas, as well as the inverse association of early life obesity with breast cancer. MR studies, which might account for lifelong adiposity, suggest that the associations in observational studies typically based on single measurement may underestimate the magnitude of the association. For lung cancer, MR studies find a positive association with obesity, supporting that the inverse association observed in some conventional observational studies likely reflects reverse causality (loss of lean body mass before diagnosis) and confounding by smoking. However, MR studies have not had sufficient power for gallbladder cancer, gastric cardia cancer, and multiple myeloma. In addition, more MR studies are needed to explore the effect of obesity at different time points on postmenopausal breast cancer and aggressive prostate cancer.

Postmenopausal overweight and breast cancer risk; results from the KARMA cohort

“…For women with overweight in early adulthood, there was instead a reduced risk of postmenopausal breast cancer, independent of later weight-gain. For women who did gain weight after early adulthood, especially leaner women, there was instead an increased risk of receptor positive breast cancer [ 4 , 29 ], which has been further validated in a recent Mendelian Randomization study [ 8 ]. Some studies have also suggested that the positive association between obesity and postmenopausal breast cancer is more pronounced in older postmenopausal women.…”

“…However, studies have identified associations with tumor angiogenesis, and an increase in proinflammatory cytokines promoting tumor growth, invasion, and metastatic potential [3]. For breast cancer, most earlier studies have found an association between obesity and risk of postmenopausal breast cancer [4][5][6][7], even though recent publications have modified the picture and suggested that the risk may be limited to women with adulthood overweight, and especially postmenopausal weight-gain, and not to women who have been overweight from childhood, as childhood overweight seems to exert a protective effect against breast cancer risk [8]. The association between specific tumor types and in overweight/obese women is, however, less clarified.…”

Excess mortality associated with elevated body weight in the USA by state and demographic subgroup: A modelling study

“…Residual confounding by smoking may also contribute to underestimation of the impacts of excess adiposity; for example, high body weight is strongly associated with lower risk of lung cancer, but there is no plausible mechanism and Mendelian randomization analyses suggest that this inverse association is not causal. 33 …”

An ecological study of obesity-related cancer incidence trends in Australia from 1983 to 2017

“…Evidence from mendelian randomisation studies reinforced causal relationships with cancers of the colorectum, endometrium, ovary, kidney, pancreas and oesophagus (adenocarcinoma) but similarly could not confirm causality for gallbladder cancer, gastric cardia cancer, and multiple myeloma, citing low power of the included studies. 35 …”