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.

Signal transduction pathway mutations in gastrointestinal (GI) cancers: a systematic review and meta-analysis

“… + 129 110 Witkiewicz 2015 USA + + + * + + 130 111 Okabe 2016 USA + + + * + + 131 112 Grellety 2016 France + + + * ? + 132 113 Jauhri 2016 India + + + * ? + 133 114 Nam 2016 Republic of Korea + + + * + + 134 115 Dallol 2016 Saudi Arabia + + + ...…”

The mutational frequency of BRAF and KRAS in low‐grade serous testicular neoplasms—a case series

“…KRAS and BRAF mutations have been previously considered to be mutually exclusive. However, colorectal carcinoma patients with coexisting KRAS and BRAF mutations have been recently described, and co‐mutation of NRAS (another member of the MAPK pathway) with KRAS has been seen in non‐small‐cell lung cancer and endometrial carcinoma . The coexistence of KRAS and BRAF mutations could be explained by genetic heterogeneity of the tumours.…”

“…In order to explore this possibility, we analysed three different parts of the tumour, all of which showed coexisting BRAF and KRAS mutations, making spatial genetic heterogeneity unlikely. Furthermore, it has been demonstrated that concomitant mutations of the genes probably occur early in tumorigenesis, and it is possible that the mutations have a synergistic effect, providing a selective advantage to the tumour cells . The effect of this event, however, is not yet established, so the significance of such co‐mutations in borderline serous testicular neoplasms remains unknown.…”

CoMutDB: the landscape of somatic mutation co-occurrence in cancers

“…Variant co-mutations with KRAS-mutant led to different effects on prognosis and chemotherapy response of NSCLC patients ( Arbour et al , 2018 ). Co-mutations among multiple MAPK pathway genes were reported in a few colorectal cancer patients ( Grellety et al , 2016 ). In a pan-cancer study ( Liu et al , 2020 ), gene pairs’ co-mutation attribute was integrated with gene co-expression topology to prioritize potential prognostic and pharmacogenomics biomarkers.…”