Abstract
RAS genotyping is mandatory to predict anti-EGFR monoclonal antibodies (mAbs) therapy resistance and BRAF genotyping is a relevant prognosis marker in patients with metastatic colorectal cancer. Although the role of hotspot mutations is well defined, the impact of uncommon mutations is still unknown. In this study, we aimed to discuss the potential utility of detecting uncommon RAS and BRAF mutation profiles with next-generation sequencing. A total of 779 FFPE samples from patients with metastatic colorectal cancer with valid NGS results were screened and 22 uncommon mutational profiles of KRAS, NRAS and BRAF genes were selected. In silico prediction of mutation impact was then assessed by 2 predictive scores and a structural protein modelling. Three samples carry a single KRAS non-hotspot mutation, one a single NRAS non-hotspot mutation, four a single BRAF non-hotspot mutation and fourteen carry several mutations. This in silico study shows that some non-hotspot RAS mutations seem to behave like hotspot mutations and warrant further examination to assess whether they should confer a resistance to anti-EGFR mAbs therapy for patients bearing these non-hotspot RAS mutations. For BRAF gene, non-V600E mutations may characterise a novel subtype of mCRC with better prognosis, potentially implying a modification of therapeutic strategy.
Highlights
Combination of targeted therapies like anti-EGFR monoclonal antibodies with chemotherapy regimen (FOLFOX or FOLFIRI) improves progression-free (PFS) and overall survival (OS) in patients with metastatic colorectal cancer[1]
Mutant allele fraction was between 1.8% and 40.6% for non-hotspot NRAS mutations, between 4.0% and 14.5% for non-hotspot KRAS mutations and between 7.9% and 46.2% for non-hotspot BRAF mutations
We assessed the value of Next generation sequencing (NGS)-based testing to identify uncommon KRAS, NRAS and BRAF mutational profiles associated to in silico projection to evaluate their therapeutic and clinical implications in 779 samples of patients with metastatic colorectal cancer (mCRC)
Summary
Combination of targeted therapies like anti-EGFR monoclonal antibodies (anti-EGFR mAbs) with chemotherapy regimen (FOLFOX or FOLFIRI) improves progression-free (PFS) and overall survival (OS) in patients with metastatic colorectal cancer (mCRC)[1]. KRAS and NRAS are both Ras serine-threonine kinases, located downstream of EGFR in the Ras/Raf/MAPK pathway Mutations in these codons cause constitutive activation of the RAS-MAPK pathway. The impact of non-hotspot mutations of KRAS, NRAS and BRAF on anti-EGFR mAbs resistance is still unclear and it may be useful to study their impact in patients with mCRC. Non-hotspot mutations have an impact on BRAF protein activity, leading to high, intermediate or impaired kinase activity[12,13]. The aim of this study was to identify isolated or concomitant non-hotspot RAS and BRAF mutations detected during routine sequencing by NGS and discuss their potential role in treatment resistance and prognosis for patients with mCRC using in silico prediction tools
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