RAS mutations affect pattern of metastatic spread and increase propensity for brain metastasis in colorectal cancer

Cancer. 2015 Apr 15;121(8):1195-203. doi: 10.1002/cncr.29196. Epub 2014 Dec 9.


Background: RAS and PIK3CA mutations in metastatic colorectal cancer (mCRC) have been associated with worse survival. We sought to evaluate the impact of RAS and PIK3CA mutations on cumulative incidence of metastasis to potentially curable sites of liver and lung and other sites such as bone and brain.

Methods: We performed a computerized search of the electronic medical record of our institution for mCRC cases genotyped for RAS or PIK3CA mutations from 2008 to 2012. Cases were reviewed for patient characteristics, survival, and site-specific metastasis.

Results: Among the 918 patients identified, 477 cases were RAS wild type, and 441 cases had a RAS mutation (394 at KRAS exon 2, 29 at KRAS exon 3 or 4, and 18 in NRAS). RAS mutation was significantly associated with shorter median overall survival (OS) and on multivariate analysis independently predicted worse OS (HR, 1.6; P < .01). RAS mutant mCRC exhibited a significantly higher cumulative incidence of lung, bone, and brain metastasis and on multivariate analysis was an independent predictor of involvement of these sites (HR, 1.5, 1.6, and 3.7, respectively). PIK3CA mutations occurred in 10% of the 786 cases genotyped, did not predict for worse survival, and did not exhibit a site-specific pattern of metastatic spread.

Conclusions: The metastatic potential of CRC varies with the presence of RAS mutation. RAS mutation is associated with worse OS and increased incidence of lung, bone, and brain metastasis. An understanding of this site-specific pattern of spread may help to inform physicians' assessment of symptoms in patients with mCRC.

Keywords: PIK3CA; RAS; colorectal cancer; neoplasm metastasis; prognosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Bone Neoplasms / genetics
  • Bone Neoplasms / secondary
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology
  • Brain Neoplasms / secondary*
  • Class I Phosphatidylinositol 3-Kinases
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Female
  • GTP Phosphohydrolases / genetics*
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / secondary
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Mutation
  • Phosphatidylinositol 3-Kinases / genetics*
  • Prognosis
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins p21(ras)
  • Survival Analysis
  • Young Adult
  • ras Proteins / genetics*


  • KRAS protein, human
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Phosphatidylinositol 3-Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • GTP Phosphohydrolases
  • NRAS protein, human
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins