Prognostic Value of Autophagy, Microsatellite Instability, and KRAS Mutations in Colorectal Cancer

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Abstract

Introduction: Autophagy plays pivotal role in various tumors, including colorectal cancer (CRC). Microsatellite instability (MSI) and KRAS mutations are also involved in response to the adjuvant therapy of CRC. We aimed to investigate the relationships among autophagy, KRAS mutations, MSI, clinicopathological parameters, and prognosis in CRC patients. Methods and Results: We tested 200 CRC tumors for autophagy-related protein expression (Beclin 1 and LC3), MSI status, and KRAS mutations. Results: Expression of Beclin 1 and LC3 was higher in CRC, with Beclin 1 significantly correlating with the depth of invasion, whereas LC3 was not associated with clinicopathological parameters. Patients expressing the LC3 proteins experienced a shorter overall survival (OS) after surgery with adjuvant therapy, especially in the MSS/L-CRC subgroup and the mutated KRAS subgroup. MSS/L-CRC patients with KRAS mutations positively expressed the LC3 protein and suffered a shorter OS than LC3 non-expressing patients. In CRC patients who received either capecitabine or capecitabine combined with oxaliplatin post-surgery, the positive expression of LC3 correlated with worse OS compared to patients who did not express LC3. Sequencing showed BRCA1/2 as the most variant genes in all patients. Nevertheless, deleterious variations were more frequent in patients with MSI-H CRC. Conclusions: High LC3 protein expression shows a certain prognostic value in CRC patients. LC3, the MSI status, and KRAS mutations must be considered when selecting an adjuvant therapy for CRC. The detection of these indexes is of great significance to identify high-risk patients who would benefit from autophagy-related anticancer drugs or help to explore more effective treatment options for patients who are resistant to conventional chemotherapy or relapse.

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