Clinico-pathological associations and concomitant mutations of the RAS/RAF pathway in metastatic colorectal cancer

Edoardo Isnaldi, Anna Garuti, Gabriella Cirmena, Stefano Scabini, Edoardo Rimini, Lorenzo Ferrando, Michela Lia, Roberto Murialdo, Lucia Tixi, Enrico Carminati, Andrea Panaro, Maurizio Gallo, Federica Grillo, Luca Mastracci, Lazzaro Repetto, Roberto Fiocca, Emanuele Romairone, Gabriele Zoppoli, Alberto Ballestrero

Research output: Contribution to journalArticlepeer-review


Background: Over the past few years, next-generation sequencing (NGS) has become reliable and cost-effective, and its use in clinical practice has become a reality. A relevant role for NGS is the prediction of response to anti-EGFR agents in metastatic colorectal cancer (mCRC), where multiple exons from KRAS, NRAS, and BRAF must be sequenced simultaneously. Methods: We optimized a 14-amplicon NGS panel to assess, in a consecutive cohort of 219 patients affected by mCRC, the presence and clinico-pathological associations of mutations in the KRAS, NRAS, BRAF, and PIK3CA genes from formalin-fixed, paraffin-embedded specimens collected for diagnostics and research at the time of diagnosis. Results: We observed a statistically significant association of RAS mutations with sex, young age, and tumor site. We demonstrated that concomitant mutations in the RAS/RAF pathway are not infrequent in mCRC, and as anticipated by whole-genome studies, RAS and PIK3CA tend to be concurrently mutated. We corroborated the association of BRAF mutations in right mCRC tumors with microsatellite instability. We established tumor side as prognostic parameter independently of mutational status. Conclusions: To our knowledge, this is the first monocentric, consecutively accrued clinical mCRC cancer cohort tested by NGS in a real-world context for KRAS, NRAS, BRAF, and PIK3CA. Our study has highlighted in clinical practice findings such as the concomitance of mutations in the RAS/RAF pathway, the presence of multiple mutations in single gene, the co-occurrence of RAS and PIK3CA mutations, the prognostic value of tumor side and possible associations of sex with specific mutations.

Original languageEnglish
Article number137
JournalJournal of Translational Medicine
Issue number1
Publication statusPublished - Apr 29 2019


  • Anti-EGFR
  • Concomitant mutations
  • Extended RAS
  • Metastatic colorectal cancer
  • RAS/RAF pathway

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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