title: Challenging a dogma: co-mutations exist in MAPK pathway genes in colorectal cancer.
abstract: Sequencing of genes encoding mitogen-activated protein kinase (MAPK) pathway proteins in colorectal cancer (CRC) has established as dogma that of the genes in a pathway only a single one is ever mutated. We searched for cases with a mutation in more than one MAPK pathway gene (co-mutations). Tumor tissue samples of all patients presenting with CRC, and referred between 01/01/2008 and 01/06/2015 to three French cancer centers for determination of mutation status of RAS/RAF+/-PIK3CA, were retrospectively screened for co-mutations using Sanger sequencing or next-generation sequencing. We found that of 1791 colorectal patients with mutations in the MAPK pathway, 20 had a co-mutation, 8 of KRAS/NRAS, and some even with a third mutation. More than half of the mutations were in codons 12 and 13. We also found 3 cases with a co-mutation of NRAS/BRAF and 9 with a co-mutation of KRAS/BRAF. In 2 patients with a co-mutation of KRAS/NRAS, the co-mutation existed in the primary as well as in a metastasis, which suggests that co-mutations occur early during carcinogenesis and are maintained when a tumor disseminates. We conclude that co-mutations exist in the MAPK genes but with low frequency and as yet with unknown outcome implications.
authors.affiliation: Department of Medical Oncology, Institut Bergonié, 229 Cours de L'Argonne, 33076, Bordeaux, France. t.grellety@bordeaux.unicancer.fr.
authors.forename: Thomas
authors.initials: T
authors.lastname: Grellety
authors.affiliation: Cancer Biobank and Tumor Biology Laboratory, Centre Hospitalier Universitaire de Bordeaux, Pessac, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Gros
authors.affiliation: Laboratory of Solid Tumor Genetics, IRCAN, Nice University Hospital, Nice, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Pedeutour
authors.affiliation: Cancer Biobank and Tumor Biology Laboratory, Centre Hospitalier Universitaire de Bordeaux, Pessac, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Merlio
authors.affiliation: Laboratory of Solid Tumor Genetics, IRCAN, Nice University Hospital, Nice, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Duranton-Tanneur
authors.affiliation: Department of Medical Oncology, Institut Bergonié, 229 Cours de L'Argonne, 33076, Bordeaux, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Italiano
authors.affiliation: Molecular Pathology Unit, Institut Bergonié, 229 Cours de L'Argonne, 33076, Bordeaux, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Soubeyran
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012189:Retrospective Studies
chemical_list: C117307:KRAS protein, human; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Co-mutation; Colorectal cancer; MAPK pathway; NRAS mutation