Early-life body mass index and risks of breast, endometrial, and ovarian cancers: a dose–response meta-analysis of prospective studies

Byun, Dohyun; Hong, Sung‐Eun; Ryu, Seaun; Nam, Yeonju; Jang, Hajin; Cho, Yoonkyoung; Keum, Na Na; Oh, Hyuncheol

doi:10.1038/s41416-021-01625-1

Cited by 16 publications

(9 citation statements)

References 83 publications

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“…In univariable MR models, both adult BMI and comparative body size at age 10 were associated with lower breast cancer risk, though only childhood comparative body size showed evidence of a direct effect on breast cancer in multivariable MR models, consistent with prior MR analysis 62 . Consistent with our findings, a recent meta-analysis of 37 prospective studies has also suggested a protective association of higher early life BMI with breast cancer risk 63 . It is therefore plausible that part of a potential adverse effect of E354Q on breast cancer risk is mediated via lower early-life adiposity, though discrepancies in findings between self-reported comparative body size and measured BMI in childhood require further exploration in future studies.…”

Section: Discussionsupporting

confidence: 93%

Genetically-proxied impaired GIPR signalling and risk of 6 cancers

Rogers

Ahlqvist

Robinson

et al. 2022

Preprint

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Background: Preclinical and human genetics studies suggest that impaired glucose-dependent insulinotropic polypeptide receptor (GIPR) signalling worsens glycaemic control. The relationship between GIPR signalling and risk of cancers influenced by impaired glucose homeostasis is unclear. Methods: We examined the association of a missense variant in GIPR, rs1800437 (E354Q), shown to impair long-term GIPR signalling and lower circulating GIP concentrations, with risk of 6 cancers influenced by impaired glucose homeostasis. Summary genetic association data on breast, colorectal, endometrial, lung, pancreatic, and renal cancer risk were obtained from GWAS consortia (235,698 cases, 333,932 controls). Replication analyses were performed in the FinnGen consortium (8,401 breast cancer cases, 99,321 controls). Colocalisation was performed to examine robustness of findings to genetic confounding. Finally, we examined the association of E354Q with potential downstream molecular mediators of GIPR signalling to identify possible mechanisms underpinning an effect on cancer risk. Results: Each copy of E354Q was associated with a higher risk of overall breast cancer (OR:1.05,95%CI:1.03-1.06,P=4.23x10-9) and luminal A-like breast cancer (OR:1.05,95%CI:1.03-1.06,P=6.02x10-7). In replication analysis, E354Q was likewise associated with breast cancer risk (OR:1.06,95%CI:1.02-1.08,P=1.09x10-3) and in colocalisation there was a >99.9% posterior probability of circulating GIP concentrations sharing a causal variant with overall and luminal A-like breast cancer in GIPR. E354Q was not associated with risk of the 5 other cancers examined. In mechanistic analysis, this variant was associated with higher postprandial glucose concentrations but diminished insulin secretion and lower testosterone concentrations. Conclusion: Our comprehensive drug target-Mendelian randomization analysis across 6 cancers suggests an adverse effect of the GIPR E354Q variant on overall and luminal A-like breast cancer risk. These findings provide genetic evidence to support further evaluation of the therapeutic potential of GIPR signalling in breast cancer prevention.

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Section: Discussionsupporting

confidence: 93%

Genetically-proxied impaired GIPR signalling and risk of 6 cancers

Rogers

Ahlqvist

Robinson

et al. 2022

Preprint

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“…Similarly, Fairfield advocated that there was no statistically significant association between overweight at the age of 18 and ovarian cancer (adjusted RR = 1.12; 95% CI: 0.77 to 1.63) through the analysis of 109,445 participants in the Nurses’ Health Study [ 18 ]. Recently, a meta-analysis from Byun and colleagues suggested that the risk of ovarian cancer increased each 15% when early-life BMI increases every 5 kg/m 2 , (RR = 1.15; 95% CI: 1.07 to 1.23), which provided high-level evidence that early-life obesity could be a significant risk factor for ovarian cancer [ 32 ]. Nevertheless, the number of included studies (6 cohort studies) was insufficient, and the data were mixed with the early adulthood results (age ≤ 25 years).…”

Section: Discussionmentioning

confidence: 99%

Obesity in children and adolescents and the risk of ovarian cancer: A systematic review and dose‒response meta-analysis

et al. 2022

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Objective The relationship between obesity in children and adolescents and the risk of ovarian cancer remains controversial. The aim of this meta-analysis was to explore the exact shape of this relationship. Methods We conducted dose‒response meta-analyses of cohort and case‒control studies, including published studies derived from searches in the PubMed, Embase, Web of Science and Cochrane Library databases until October 2022. Pooled effect size estimates are expressed as relative risks (RRs) or odds ratios (ORs) with 95% confidence intervals (CIs) and were evaluated by fixed-effect models. A nonlinear dose‒response meta-analysis was performed by using a restricted cubic spline model. Results After screening 4215 publications, 10 studies were included in the present meta-analysis. Overall analyses revealed statistically significant associations of obesity in children and adolescents with ovarian cancer (adjusted RR = 1.19, 95% CI: 1.11 to 1.28, P < 0.001). Moreover, the association was consistently significant in most subgroup analyses, for example, using geographic stratification, the results remained stable both in the Americas(RR = 1.11; 95% CI: 1.01 to 1.21; P = 0.022) and Europe (RR = 1.46; 95% CI: 1.21 to 1.77; P<0.001). For the dose‒response analyses, the risk of ovarian cancer increased with the degree of obesity, and the trend increased rapidly when body mass index (BMI) was over 25.95 kg/m2. Conclusion Our findings indicate that obesity in children and adolescents is a risk factor for ovarian cancer, and the risk increases with increasing BMI.

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“…The directional consistent results derived from multiple ‘pleiotropy-robust’ methods 42 supported the validity of our MR results. Lastly, as two-sample MR approach is typically based on linear assumption, we were unable to examine the nonlinear obesity-BC relationship based on GWAS summary statistics, such as the N-shaped association which was identified in traditional epidemiological studies 45 , 46 . Future one-sample MR studies using semiparametric methods 44 are perhaps warranted.…”

Section: Discussionmentioning

confidence: 99%

Reassessing the causal role of obesity in breast cancer susceptibility: a comprehensive multivariable Mendelian randomization investigating the distribution and timing of exposure

Xiao

Liang

et al. 2022

International Journal of Epidemiology

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Background Previous Mendelian randomization (MR) studies on obesity and risk of breast cancer adopted a small number of instrumental variables and focused mainly on the crude total effect. We aim to investigate the independent causal effect of obesity on breast cancer susceptibility, considering the distribution of fat, covering both early and late life. Methods Using an enlarged set of female-specific genetic variants associated with adult general [body mass index (BMI)] and abdominal obesity [waist-to-hip ratio (WHR) with and without adjustment for BMI, WHR and WHRadjBMI] as well as using sex-combined genetic variants of childhood obesity (childhood BMI), we performed a two-sample univariable MR to re-evaluate the total effect of each obesity-related exposure on overall breast cancer (Ncase = 133 384, Ncontrol = 113 789). We further looked into its oestrogen receptor (ER)-defined subtypes (NER+ = 69 501, NER– = 21 468, Ncontrol = 105 974). Multivariable MR was applied to estimate the independent causal effect of each obesity-related exposure on breast cancer taking into account confounders as well as to investigate the independent effect of adult and childhood obesity considering their inter-correlation. Results In univariable MR, the protective effects of both adult BMI [odds ratio (OR) = 0.89, 95% CI = 0.83–0.96, P = 2.06 × 10−3] and childhood BMI (OR = 0.78, 95% CI = 0.70–0.87, P = 4.58 × 10−6) were observed for breast cancer overall. Comparable effects were found in ER+ and ER− subtypes. Similarly, genetically predicted adult WHR was also associated with a decreased risk of breast cancer overall (OR = 0.87, 95% CI = 0.80–0.96, P = 3.77 × 10−3), restricting to ER+ subtype (OR = 0.88, 95% CI = 0.80–0.98, P = 1.84 × 10−2). Conditional on childhood BMI, the effect of adult general obesity on breast cancer overall attenuated to null (BMI: OR = 1.00, 95% CI = 0.90–1.10, P = 0.96), whereas the effect of adult abdominal obesity attenuated to some extent (WHR: OR = 0.90, 95% CI = 0.82–0.98, P = 1.49 × 10–2; WHRadjBMI: OR = 0.92, 95% CI = 0.86–0.99, P = 1.98 × 10–2). On the contrary, an independent protective effect of childhood BMI was observed in breast cancer overall, irrespective of adult measures (adjusted for adult BMI: OR = 0.84, 95% CI = 0.77–0.93, P = 3.93 × 10–4; adjusted for adult WHR: OR = 0.84, 95% CI = 0.76–0.91, P = 6.57 × 10–5; adjusted for adult WHRadjBMI: OR = 0.80, 95% CI = 0.74–0.87, P = 1.24 × 10–7). Conclusion Although successfully replicating the inverse causal relationship between adult obesity-related exposures and risk of breast cancer, our study demonstrated such effects to be largely (adult BMI) or partly (adult WHR or WHRadjBMI) attributed to childhood obesity. Our findings highlighted an independent role of childhood obesity in affecting the risk of breast cancer as well as the importance of taking into account the complex interplay underlying correlated exposures.

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Early-life body mass index and risks of breast, endometrial, and ovarian cancers: a dose–response meta-analysis of prospective studies

Cited by 16 publications

References 83 publications

Genetically-proxied impaired GIPR signalling and risk of 6 cancers

Genetically-proxied impaired GIPR signalling and risk of 6 cancers

Obesity in children and adolescents and the risk of ovarian cancer: A systematic review and dose‒response meta-analysis

Reassessing the causal role of obesity in breast cancer susceptibility: a comprehensive multivariable Mendelian randomization investigating the distribution and timing of exposure

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