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Intratumorous heterogeneity for RAS mutations in a treatment-naïve colorectal tumour
  1. Sebastian Lunke1,
  2. Belinda Lee2,
  3. Sevastjan Kranz3,
  4. Peter Gibbs2,4,
  5. Paul Waring1,
  6. Michael Christie1,2,3
  1. 1Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
  2. 2Colorectal Translational Oncology Group, Walter and Eliza Hall Institute, Parkville, Victoria, Australia
  3. 3Department of Pathology, Royal Melbourne Hospital, Parkville, Victoria, Australia
  4. 4Department of Medical Oncology, Royal Melbourne Hospital, Parkville, Victoria, Australia
  1. Correspondence to Dr Sebastian Lunke, Department of Pathology, University of Melbourne, Parkville, VIC 3010, Australia; Sebastian.Lunke{at}


Activating mutations in KRAS and NRAS genes in patients with colorectal cancer (CRC) are associated with a lack of response to treatment with anti-epidermal growth factor receptor (EGFR) therapies. Mutations in these genes are thought to be mutually exclusive, however reports have described CRCs with two activating rat sarcoma (RAS) mutations. This has fuelled discussion about whether these mutations are the result of intratumorous heterogeneity, or if they are co-occurring in the same cancer cell clone. We present a case of a colorectal tumour with three RAS mutations detected during routine diagnostic testing. Further detailed analysis with laser capture microdissection and next generation sequencing excluded the possibility of all three mutations being present in the same clone, presenting the highest resolution evidence of intratumorous heterogeneity of RAS mutations to date.


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  • Handling editor Runjan Chetty

  • Contributors SL and MC are the primary authors and guarantors of the manuscript and were responsible for the majority of data generation and analysis. BL and SK contributed in data generation and assembly. PG and PW contributed in the interpretation of the results.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.