Deleterious Effect of RAS and Evolutionary High-risk TP53 Double Mutation in Colorectal Liver Metastases

Abstract

Objective: To assess the impact of somatic gene mutations on survival among patients undergoing resection of colorectal liver metastases (CLM).

Background: Patients undergoing CLM resection have heterogeneous outcomes, and accurate risk stratification is necessary to optimize patient selection for surgery.

Methods: Next-generation sequencing of 50 cancer-related genes was performed from primary tumors and/or liver metastases in 401 patients undergoing CLM resection. Missense TP53 mutations were classified by the evolutionary action score (EAp53)-a novel approach that dichotomizes mutations as low or high risk.

Results: The most frequent somatic gene mutations were TP53 (65.6%), followed by KRAS (48.1%) and APC (47.4%). Double mutation in RAS/TP53, identified in 31.4% of patients, was correlated with primary tumor location in the right colon (P = 0.006). On multivariable analysis, RAS/TP53 double mutation was an independent predictor of shorter overall survival (hazard ratio 2.62, 95% confidence interval 1.41-4.87, P = 0.002). In patients with co-mutated RAS, EAp53 high-risk mutations were associated with shorter 5-year overall survival of 12.2%, compared with 55.7% for TP53 wild type (P < 0.001). The negative prognostic effects of RAS and TP53 mutations were limited to tumors harboring mutations in both genes.

Conclusions: Concomitant RAS and TP53 mutations are associated with decreased survival after CLM resection. A high EAp53 predicts a subset of patients with worse prognosis. These preliminary analyses suggest that surgical resection of liver metastases should be carefully considered in this subset of patients.

Figure 1.

(A) Prevalence of somatic gene mutations among 401 patients undergoing resection of colorectal liver metastases. (B) Co-mutation plot showing patients in columns and genes in rows. Red blocks represent somatic mutations or deficient mismatch repair status. Blue blocks represent absence of somatic mutations or intact mismatch repair. Microsatellite instability status was not available for 20 patients, represented by white blocks. MSI-H, microsatellite instability-high.

Figure 2.

Relationship between RAS and TP53 mutations and overall survival after resection of colorectal liver metastases. Analysis of the entire patient cohort demonstrated a significant association between overall survival and RAS mutations (A) but not TP53 mutations (B). Stratification by both mutations revealed that TP53 mutations were significantly associated with overall survival among patients with concomitant RAS mutations (C). Similarly, the negative prognostic effect of RAS mutations was limited to patients with concurrent TP53 mutations. Recurrence-free survival was decreased in patients with double mutation in RAS/TP53 (D). Wt, wild-type; mut, mutated.

Figure 3.

(A) Lolliplots showing distribution of somatic mutations in TP53 in 263 patients undergoing resection of colorectal liver metastases. (B) Overall survival by type of TP53 mutation (n = 399). Two patients with TP53 in-frame deletions were omitted from analysis. (C) Overall survival among RAS mutated patients, by type of TP53 mutation (n = 209). EAp53, Evolutionary Action of p53; W, TP53 wild-type; T/L, truncating or EAp53 low risk mutation; H, EAp53 high risk mutation; mut, mutation.