KRAS, NRAS, and BRAF mutation prevalence, clinicopathological association, and their application in a predictive model in Mexican patients with metastatic colorectal cancer: A retrospective cohort study

PLoS One. 2020 Jul 6;15(7):e0235490. doi: 10.1371/journal.pone.0235490. eCollection 2020.

Abstract

Mutations in KRAS, NRAS, and BRAF (RAS/BRAF) genes are the main predictive biomarkers for the response to anti-EGFR monoclonal antibodies (MAbs) targeted therapy in metastatic colorectal cancer (mCRC). This retrospective study aimed to report the mutational status prevalence of these genes, explore their possible associations with clinicopathological features, and build and validate a predictive model. To achieve these objectives, 500 mCRC Mexican patients were screened for clinically relevant mutations in RAS/BRAF genes. Fifty-two percent of these specimens harbored clinically relevant mutations in at least one screened gene. Among these, 86% had a mutation in KRAS, 7% in NRAS, 6% in BRAF, and 2% in both NRAS and BRAF. Only tumor location in the proximal colon exhibited a significant correlation with KRAS and BRAF mutational status (p-value = 0.0414 and 0.0065, respectively). Further t-SNE analyses were made to 191 specimens to reveal patterns among patients with clinical parameters and KRAS mutational status. Then, directed by the results from classical statistical tests and t-SNE analysis, neural network models utilized entity embeddings to learn patterns and build predictive models using a minimal number of trainable parameters. This study could be the first step in the prediction for RAS/BRAF mutational status from tumoral features and could lead the way to a more detailed and more diverse dataset that could benefit from machine learning methods.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cohort Studies
  • Colorectal Neoplasms / epidemiology
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology*
  • Female
  • GTP Phosphohydrolases / genetics*
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Mexico / epidemiology
  • Middle Aged
  • Models, Statistical*
  • Mutation Rate*
  • Neural Networks, Computer
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Retrospective Studies

Substances

  • KRAS protein, human
  • Membrane Proteins
  • Proto-Oncogene Proteins B-raf
  • GTP Phosphohydrolases
  • NRAS protein, human
  • Proto-Oncogene Proteins p21(ras)