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Background: The incidence of early-onset colorectal cancer (EOCRC) rose abruptly in the mid 1990s, is continuing to increase, and has now been noted in many countries. By 2030, 25% of American patients diagnosed with rectal cancer will be 49 years or younger. The large majority of EOCRC cases are not found in patients with germline cancer susceptibility mutations (eg, Lynch syndrome) or inflammatory bowel disease. Thus, environmental or lifestyle factors are suspected drivers. Obesity, sedentary lifestyle, diabetes mellitus, smoking, alcohol, or antibiotics affecting the gut microbiome have been proposed. However, these factors, which have been present since the 1950s, have not yet been conclusively linked to the abrupt increase in EOCRC. The sharp increase suggests the introduction of a new risk factor for young people. We hypothesized that the driver may be an off-target effect of a pharmaceutical agent (ie, one requiring regulatory approval before its use in the general population or an off-label use of a previously approved agent) in a genetically susceptible subgroup of young adults. If a pharmaceutical agent is an EOCRC driving factor, regulatory risk mitigation strategies could be used., Objective: We aimed to evaluate the possibility that pharmaceutical agents serve as risk factors for EOCRC., Methods: We conducted a case-control study. Data including demographics, comorbidities, and complete medication dispensing history were obtained from the electronic medical records database of Maccabi Healthcare Services, a state-mandated health provider covering 26% of the Israeli population. The participants included 941 patients with EOCRC (≤50 years of age) diagnosed during 2001-2019 who were density matched at a ratio of 1:10 with 9410 control patients. Patients with inflammatory bowel disease and those with a known inherited cancer susceptibility syndrome were excluded. An advanced machine learning algorithm based on gradient boosted decision trees coupled with Bayesian model optimization and repeated data sampling was used to sort through the very high-dimensional drug dispensing data to identify specific medication groups that were consistently linked with EOCRC while allowing for synergistic or antagonistic interactions between medications. Odds ratios for the identified medication classes were obtained from a conditional logistic regression model., Results: Out of more than 800 medication classes, we identified several classes that were consistently associated with EOCRC risk across independently trained models. Interactions between medication groups did not seem to substantially affect the risk. In our analysis, drug groups that were consistently positively associated with EOCRC included beta blockers and valerian (Valeriana officinalis). Antibiotics were not consistently associated with EOCRC risk., Conclusions: Our analysis suggests that the development of EOCRC may be correlated with prior use of specific medications. Additional analyses should be used to validate the results. The mechanism of action inducing EOCRC by candidate pharmaceutical agents will then need to be determined., (©Irit Ben-Aharon, Ran Rotem, Cheli Melzer-Cohen, Gilad Twig, Andrea Cercek, Elizabeth Half, Tal Goshen-Lago, Gabriel Chodik, David Kelsen. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 13.12.2023.)