Dataset Information

Body Shape Phenotypes and Breast Cancer Risk: A Mendelian Randomization Analysis.

ABSTRACT: Observational and genetic studies have linked different anthropometric traits to breast cancer (BC) risk, with inconsistent results. We aimed to investigate the association between body shape defined by a principal component (PC) analysis of anthropometric traits (body mass index [BMI], height, weight, waist-to-hip ratio [WHR], and waist and hip circumference) and overall BC risk and by tumor sub-type (luminal A, luminal B, HER2+, triple negative, and luminal B/HER2 negative). We performed two-sample Mendelian randomization analyses to assess the association between 188 genetic variants robustly linked to the first three PCs and BC (133,384 cases/113,789 controls from the Breast Cancer Association Consortium (BCAC)). PC1 (general adiposity) was inversely associated with overall BC risk (0.89 per 1 SD [95% CI: 0.81-0.98]; p-value = 0.016). PC2 (tall women with low WHR) was weakly positively associated with overall BC risk (1.05 [95% CI: 0.98-1.12]; p-value = 0.135), but with a confidence interval including the null. PC3 (tall women with large WHR) was not associated with overall BC risk. Some of these associations differed by BC sub-types. For instance, PC2 was positively associated with a risk of luminal A BC sub-type (1.09 [95% CI: 1.01-1.18]; p-value = 0.02). To clarify the inverse association of PC1 with breast cancer risk, future studies should examine independent risk associations of this body shape during childhood/adolescence and adulthood.

SUBMITTER: Peruchet-Noray L

PROVIDER: S-EPMC9954632 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

Body Shape Phenotypes and Breast Cancer Risk: A Mendelian Randomization Analysis.

Peruchet-Noray Laia L Dimou Niki N Sedlmeier Anja M AM Fervers Béatrice B Romieu Isabelle I Viallon Vivian V Ferrari Pietro P Gunter Marc J MJ Carreras-Torres Robert R Freisling Heinz H

Cancers 20230217 4

Observational and genetic studies have linked different anthropometric traits to breast cancer (BC) risk, with inconsistent results. We aimed to investigate the association between body shape defined by a principal component (PC) analysis of anthropometric traits (body mass index [BMI], height, weight, waist-to-hip ratio [WHR], and waist and hip circumference) and overall BC risk and by tumor sub-type (luminal A, luminal B, HER2+, triple negative, and luminal B/HER2 negative). We performed two-s ...[more]

PMID: 36831637

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Project description:The Rho GTPase family consists of 20 genes encoding intracellular signalling proteins that influence cytoskeletal dynamics, cell migration and cell cycle progression. They are implicated in breast cancer progression but their role in breast cancer aetiology is unknown. As aberrant Rho GTPase activity could be associated with breast cancer, we aimed to determine the potential for a causal role of Rho GTPase gene expression in breast cancer risk, using two-sample Mendelian randomization (MR). MR was undertaken in 122,977 breast cancer cases and 105,974 controls, including 69,501 estrogen receptor positive (ER+) cases and 105,974 controls, and 21,468 ER negative (ER-) cases and 105,974 controls. Single nucleotide polymorphisms (SNPs) underlying expression quantitative trait loci (eQTLs) obtained from normal breast tissue, breast cancer tissue and blood were used as genetic instruments for Rho GTPase expression. As a sensitivity analysis, we undertook co-localisation to examine whether findings reflected shared causal variants or genomic confounding. We identified genetic instruments for 14 of the 20 human Rho GTPases. Using eQTLs obtained from normal breast tissue and normal blood, we identified evidence of a causal role of RHOD in overall and ER+ breast cancers (overall breast cancer: odds ratio (OR) per standard deviation (SD) increase in expression level 1.06; (95% confidence interval (CI) 1.03, 1.09; P = 5.65 × 10-5) and OR 1.22 (95% CI 1.11, 1.35; P = 5.22 × 10-5) in normal breast tissue and blood respectively). There was a consistent direction of association for ER- breast cancer, although the effect-estimate was imprecisely estimated. Using eQTLs from breast cancer tissue and normal blood there was some evidence that CDC42 was negatively associated with overall and ER + breast cancer risk. The evidence from colocalization analyses strongly supported our MR results particularly for RHOD. Our study suggests a potential causal role of increased RHOD gene expression, and, although the evidence is weaker, a potential protective role for CDC42 gene expression, in overall and ER+ breast cancers. These finding warrant validation in independent samples and further biological investigation to assess whether they may be suitable targets for drug targeting.

Dataset Information

Body Shape Phenotypes and Breast Cancer Risk: A Mendelian Randomization Analysis.

Publications

Body Shape Phenotypes and Breast Cancer Risk: A Mendelian Randomization Analysis.

Similar Datasets

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