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

Ann Surg. 2019 May;269(5):917-923. doi: 10.1097/SLA.0000000000002450.


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.

MeSH terms

  • Adult
  • Aged
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology*
  • Female
  • GTP Phosphohydrolases / genetics*
  • Hepatectomy*
  • Humans
  • Liver Neoplasms / mortality
  • Liver Neoplasms / secondary*
  • Liver Neoplasms / surgery*
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Mutation*
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Risk Assessment
  • Survival Rate
  • Tumor Suppressor Protein p53 / genetics*
  • Young Adult


  • KRAS protein, human
  • Membrane Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • GTP Phosphohydrolases
  • NRAS protein, human
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)