Our prospective study tested an “a priori” hypothesis and met several Bradford-Hill criteria to infer causality: (i) the consistency of the association across genetic, epigenetic and in-silico analyses; (ii) temporality, genetic variability preceding colorectal carcinogenesis; (iii) plausibility based on the aforementioned experimental studies [2–4, 13] and the observation that there is an inverse association between the risk of colorectal cancer and the use of aspirin [11]; and (iv) analogy observed with genetic variability in PTEN [33–35], which is directly regulated by PEAR1 [4]. The gene discussed is PTEN; the disease is colorectal cancer.