J Cancer 2021; 12(12):3515-3528. doi:10.7150/jca.51430

Research Paper

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

Yuanyuan Wang1*, Zhi Zhao2*, Jing Zhuang3, Xinxin Wu4, Zhizhong Wang4, Bing Zhang1, Ge Gao1, Yinping Zhang1, Caili Guo5✉, Qingxin Xia1✉

1. Department of Pathology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, 127 Dongming Road, Zhengzhou 450008, China.
2. Department of Pathology, Yihe Hospital, Henan University, No. 69 Agriculture East Road, Zhengzhou 450008, China.
3. Department of General Surgery, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, 127 Dongming Road, Zhengzhou 450008, China.
4. Department of Molecular Pathology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, 127 Dongming Road, Zhengzhou 450008, China.
5. Department of Critical Care Medicine, Affiliated Children's Hospital of Zhengzhou University, No. 255 Gangdu Road, Dongsan Street, Zhengzhou 450008, China.
* These two authors contributed equally to this work and thus are regarded as co-first authors.

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Citation:
Wang Y, Zhao Z, Zhuang J, Wu X, Wang Z, Zhang B, Gao G, Zhang Y, Guo C, Xia Q. Prognostic Value of Autophagy, Microsatellite Instability, and KRAS Mutations in Colorectal Cancer. J Cancer 2021; 12(12):3515-3528. doi:10.7150/jca.51430. Available from https://www.jcancer.org/v12p3515.htm

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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.

Keywords: Beclin 1, LC3, MSI, KRAS, prognosis, CRC.