A novel 4-gene prognostic signature for hypermutated colorectal cancer

Weiting Ge; Wen Cai; Rui Bai; Wangxiong Hu; Dehao Wu; Shu Zheng; Hanguang Hu

doi:10.2147/CMAR.S190963

A novel 4-gene prognostic signature for hypermutated colorectal cancer

Cancer Manag Res. 2019 Mar 4:11:1985-1996. doi: 10.2147/CMAR.S190963. eCollection 2019.

Authors

Weiting Ge¹, Wen Cai^{1

2}, Rui Bai¹, Wangxiong Hu¹, Dehao Wu^{1

2}, Shu Zheng¹, Hanguang Hu^{1

2}

Affiliations

¹ Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China, huhanguang@zju.edu.cn.
² Department of Medical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China, huhanguang@zju.edu.cn.

Abstract

Background: Hypermutated colorectal cancer (CRC) reportedly accounts for 15%-17% of all cases of CRC. However, the proportion and number of patients with hypermutated CRC cannot be unappreciated. Additionally, therapy options for these patients differ from those for CRC patients, with a greater potential benefit from immunotherapy.

Materials and methods: We sequenced the tumor mucosa of CRC patients with >24 months of follow-up data at our center and identified mutation profiles of hypermutated CRC as a training data set (Zhejiang University [ZJU]); we then collected patients from The Cancer Genome Atlas (TCGA) as a validation data set. Recurrently mutated genes were combined to calculate a compound score via Cox proportional hazards model. Patients with higher-than-median scores were segregated as the high-risk group. Outcomes were analyzed by Kaplan-Meier and Cox regression analyses using Python (3.6.0) and R (3.4.0).

Results: We constructed a 4-gene signature (ACVR2A, APC, DOCK2, and POLE), with training in 45 hypermutated patients at ZJU and validation in 24 hypermutated patients from TCGA. Patients in the high-risk group showed poor survival (adjusted HR =9.85, 95% CI: 2.07-46.81, P=0.004). Further subgroup analysis was performed for stage II and III colon cancer (HR =10.91, 95% CI: 1.36-87.5, P=0.005) and high microsatellite instability (MSI-H) CRC (HR =12.57, 95% CI: 1.57-100.69, P=0.002) subgroups, which verified that our signature is universal. We then compared our prognostic signature with other risk factors (including MSI status, POLE driver mutation, BRAF-p.V600E, tumor mutational burden, and TNM staging). The results proved that our 4-gene signature is better than the other risk factor for prognosis in hypermutated CRC.

Conclusion: Our 4-gene signature is a good predictor of survival for hypermutated CRC, and this signature is powerful in stage II and III colon cancer and MSI-H CRC. Future prospective studies are needed to confirm the power of the 4-gene signature in patients receiving immunotherapy.

Keywords: colorectal cancer; gene signature; hypermutation; prognosis.