Multiomic quantification of the KRAS mutation dosage improves the preoperative prediction of survival and recurrence in patients with pancreatic ductal adenocarcinoma

Abstract

Most cancer mutation profiling studies are laboratory-based and lack direct clinical application. For clinical use, it is necessary to focus on key genes and integrate them with relevant clinical variables. We aimed to evaluate the prognostic value of the dosage of the KRAS G12 mutation, a key pancreatic ductal adenocarcinoma (PDAC) variant and to investigate the biological mechanism of the prognosis associated with the dosage of the KRAS G12 mutation. In this retrospective cohort study, we analyzed 193 surgically treated patients with PDAC between 2009 and 2016. RNA, whole-exome, and KRAS-targeted sequencing data were used to estimate the dosage of the KRAS G12 mutant. Our prognostic scoring system included the mutation dosage from targeted sequencing (> 0.195, 1 point), maximal tumor diameter at preoperative imaging (> 20 mm, 1 point), and carbohydrate antigen 19-9 levels (> 150 U/mL, 1 point). The KRAS mutation dosage exhibited comparable performance with clinical variables for survival prediction. High KRAS mutation dosages activated the cell cycle, leading to high mutation rates and poor prognosis. According to prognostic scoring systems that integrate mutation dosage with clinical factors, patients with 0 points had superior median overall survival of 97.0 months and 1-year, 3-year, and 5-year overall survival rates of 95.8%, 70.8%, and 66.4%, respectively. In contrast, patients with 3 points had worse median overall survival of only 16.0 months and 1-year, 3-year, and 5-year overall survival rates of 65.2%, 8.7%, and 8.7%, respectively. The incorporation of the KRAS G12 mutation dosage variable into prognostic scoring systems can improve clinical variable-based survival prediction, highlighting the feasibility of an integrated scoring system with clinical significance.