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Background: Colorectal cancer (CRC) is the third most common cancer worldwide and the third leading cause of cancer-related death. It is a heterogeneous disease that develops through different genetic and epigenetic mechanisms. To date, no comprehensive systematic review investigating genetic risk factors for familial and sporadic CRC has been performed on the extended MENA (eMENA) region., Aims: This study aimed to systematically analyze genetic variations significantly associated with CRC in the eMENA region., Methods: We searched four literature databases (PubMed, Scopus, Science Direct, and Web of Science) from the time of inception until May 2019 using broad search terms to obtain all reported genetic data related to eMENA patients with CRC. Variants with an OR>1 that are associated with CRC were identified., Results: A total of 1,200 studies were obtained from our search method, 27 of which met the inclusion criteria for our systematic review, with a total of 8,230 CRC patients and 7,611 controls. Of these, 1,941 patients distributed throughout nine eMENA countries were found to carry 46 variants in 33 different genes. Interestingly, 19 variants were unique to CRC patients in the eMENA region., Interpretation: This is the first systematic review to capture the spectrum of variants significantly associated with CRC in the eMENA region. There appears to be a distinctive clinical picture for eMENA patients with CRC, and the range and distribution of variants among patients from the eMENA region differ from those noted in other ethnic groups., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)