Our aim was to extend on the existing evidence by studying mTOR-PI3K-Akt pathway genetic variation in relation to CRC risk and by investigating potential effect modification of mTOR-PI3K-Akt pathway genetic variation on associations between energy balance-related factors (body mass index, trouser/skirt size, height, physical activity, and early life energy restriction) and CRC risk in the large, prospective Netherlands Cohort Study. This evidence concerns the gene PIK3CA and colorectal carcinoma.