Constructing Gene Prognostic Signature For Hypermutated Colorectal Caner

Objective:Colorectal cancer(CRC)is one of the most common cancer in the world,which could be divided into hypermutated type and non-hypermutated type according to the tumor mutation burden.As previous studies reported,hypermutated colorectal cancer account for approximately 15%-17%among all.The number of patients with hypermutated CRC cannot be underrated.Additionally,hypermutated patients’ option of therapy are different,who have a greater potential benefit from immunotherapy.Materials and methods:We sequenced tumor mucosa of CRC patients with more than 24-month follow up data in our center and identified mutation profiles of the hypermutated CRC as the training dataset(ZJU).Recurrently mutated genes were chosen and combined to calculate a compound score by summation of a Cox PH weighted sum of mutations using R(3.6.0)and Python(3.4.0).Patients were separated into two risk groups by the gene model:high-risk group and low risk groups.We obtained patients from The Cancer Genome Atlas(TCGA)as the validation dataset to verify the gene signature and showed the results of gene signature by pooling all patients.Results:We constructed a 4-gene signature(ACVR2A,APC,DOCK2 and POLE),training in 45 hypermutated patients in ZJU and validating in 24 hypermutated patients in TCGA.Patients of high-risk group showed worse survival(adjusted HR=9.85,95%CI:2.07-46.81,P=0.004).Further subgroup analysis was performed in stage II and stage III colon cancer(HR= 10.91,95%CI:1.36-87.50,P=0.005)and MSI colorectal cancer patients(HR=12.57,95%CI:1.57-100.69,P=0.002),which verified our model is universal.Conclusions:We constructed a gene signature to predict the prognosis of hypermutated colorectal cancer.This model is powerful in stage II and III colon cancer and MSI colorectal cancer.Future prospective studies are needed to confirm the power of 4-gene model in patients receiving immunotherapy.