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Published on: September 25, 2011
A novel 4-gene prognostic signature for hypermutated colorectal cancer
Weiting Ge1, Wen Cai1,2, Rui Bai1
1Cancer 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.
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.
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