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.
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The authors thank Dr. Ravi Nookala of Institut Bergonié for medical writing service.
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The present study was approved by the local ethics committee.
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This study was funded by the Institut Bergonié Comprehensive Cancer Center Institution.
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The authors declare that they have no conflict of interest.
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Grellety, T., Gros, A., Pedeutour, F. et al. Challenging a dogma: co-mutations exist in MAPK pathway genes in colorectal cancer. Virchows Arch 469, 459–464 (2016). https://doi.org/10.1007/s00428-016-1991-0
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DOI: https://doi.org/10.1007/s00428-016-1991-0