Somatic Mutation Profile Among Young-Onset Primary Colorectal Cancer in Palestine

   Colorectal cancer (CRC) is considered a major cause for morbidity and mortality in the world and is being more frequently diagnosed in young adults. Young CRC patients have more aggressive tumors and a poor clinical course. In this research project, we aim to elucidate the molecular alterations and somatic mutations leading to the development of non-hereditary CRC among young Palestinians. In addition, we will study the prevalence of KRAS somatic mutation in all CRC cases diagnosed in the West Bank in the past 3 years.

   Molecular alterations leading to oncogenecity in CRC can be either of hereditary but most commonly of sporadic origin. Sporadic colorectal cancers frequently arise from preneoplastic lesions through the activation of oncogenes (KRAS and BRAF); the inactivation of tumour suppressor genes (APC, p16, p53, and DCC) or mismatch repair genes, such as MLH1 and MSH2 and others.

   Activation of the KRAS signaling pathway impairs the response of metastatic colorectal cancers to anti-EGFR antibody therapies. Approximately 15% of CRC display a defect in the mismatch repair pathway, resulting in microsatellite instability (MSI). MSI tumors have a better stage-adjusted survival and may respond differently to chemotherapy.

   This project is a continuum of a multi-center, multistage collaborative research to elucidate the molecular bases of CRC. We created a CRC database, and we performed clinical, pathological and proteomic characterization of all cases since 2014. Among the 617 enrolled cases, 113 (18%) patients presented with CRC before the age 50. Hereditary forms of the disease are identified, and we are performing Next Generation Sequencing (NGS) to identify germline mutations leading to Lynch Syndrome. Next, we aim to study somatic mutations in young CRC patients. Altogether, we hope to create a molecular database of CRC among Palestinians that help better characterize the disease, identify the etiology, and guide in establishing population-based management guidelines.