Empirical Investigation of Genomic Clusters Associated with Height and the Risk of Postmenopausal Breast and Colorectal Cancer in the Netherlands Cohort Study

We empirically investigated genomic clusters associated with both height and postmenopausal breast cancer (BC) or colorectal cancer (CRC) (or both) in the Netherlands Cohort Study to unravel shared underlying mechanisms between height and these cancers. The Netherlands Cohort Study (1986-2006) includes 120,852 participants (case-cohort: nsubcohort=5000; 20.3 years follow-up). Variants in clusters on chromosomes 2, 4, 5, 6 (two clusters), 10, and 20 were genotyped using toenail DNA. Cluster-specific genetic risk scores were modelled in relation to height and postmenopausal BC and CRC risk using age-adjusted linear regression and multivariable-adjusted Cox regression, respectively. Only the chromosome 10 cluster risk score was associated with all three phenotypes in the same sex (women), i.e. it was associated with an increased height (Beta: 0.34, p-value: 0.014), an increased risk of hormone receptor-positive BC (HRcontinuous for estrogen receptor-positive BC: 1.10, 95% CI: 1.02-1.20; HRcontinuous for progesterone receptor-positive BC: 1.15, 95% CI: 1.04-1.26), and an increased risk of colon (HRcontinuous: 1.13, 95% CI: 1.01-1.27) and rectal cancer (HRcontinuous: 1.14, 95% CI: 0.94-1.30). The chromosome 10 cluster variants were all annotated to ZMIZ1 ("Zinc Finger MIZ-Type Containing 1"), involved in androgen receptor activity, suggesting hormone-related growth mechanisms could influence both height and postmenopausal BC and CRC.