Abstract Background: Colorectal cancer (CRC) is one of the commonest cancer worldwide and ranks as the most common cancer in males and the third most common among females in Saudi Arabia. Wnt pathway alteration is well known in colorectal cancer. In this study we aimed to comprehensively study Wnt pathway alterations in a large cohort of Middle Eastern colorectal patients and to know its role in this unique ethnic group. Methods: 426 CRC cases were analyzed for APC, AXIN2 and CTNNB1 somatic mutations by targeted capture sequencing and protein expression status by immunohistochemistry in tissue microarray format. Results were analyzed for association with any clinicopathological parameters and for prognostic significance. Results: The incidence of APC, AXIN2 and CTNNB1 mutations in our patient cohort were 58.2%, 4.2% and 3.8% respectively. APC mutation was associated with grade 2 tumors (p=0.0494) and male sex (p=0.0349). AXIN2 mutation were associated with grade 3 tumors (p=0.0231), MSI-high tumors (p<0.0001) and AXIN2 protein expression loss (p=0.0056). CTNNB1 mutations were associated with MSI-high tumors (p=0.0076). AXIN2 and CTNNB1 mutation were significantly associated with each other (p=0.0263). Wild type APC was associated with poor overall survival and was an independent marker of poor prognosis in late stage CRC (p=0.0200). Conclusion: We reported the incidence of Wnt pathway alterations in this unique ethnic group on which such data is lacking. APC mutation plays major and other genes minor role in Wnt pathway activation. Incidence of APC mutation in this group is comparatively high compared to reported incidence worldwide. Wild type APC independently predicts poor prognosis in Middle Eastern late stage colorectal patients. Citation Format: Abdul K. Siraj, Rong Bu, Shaham Beg, Tariq Masoodi, Khawla S. Al-Kuraya. Wild type APC is an independent marker of poor prognosis in late stage colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4641. doi:10.1158/1538-7445.AM2017-4641