Abstract
Since the advent of monoclonal antibodies against epidermal growth factor receptor (EGFR) in colorectal cancer therapy, the determination of RAS mutational status is needed for therapeutic decision-making. Most prevalent in colorectal cancer are KRAS exon 2 mutations (40% prevalence); lower prevalence is observed for KRAS exon 3 and 4 mutations (6%) and NRAS exon 2, 3, and 4 mutations (5%). The Idylla™ KRAS Mutation Test on the molecular diagnostics Idylla™ platform is a simple (<2 minutes hands-on time), highly reliable, and rapid (approximately 2 hours turnaround time) in vitro diagnostic sample-to-result solution. This test enables qualitative detection of 21 mutations in codons 12, 13, 59, 61, 117, and 146 of the KRAS oncogene being clinically relevant according to the latest clinical guidelines. Here, the performance of the Idylla™ KRAS Mutation Assay, for Research Use Only, was assessed on archived formalin-fixed paraffin-embedded (FFPE) tissue sections by comparing its results with the results previously obtained by routine reference approaches for KRAS genotyping. In case of discordance, samples were assessed further by additional methods. Among the 374 colorectal cancer FFPE samples tested, the overall concordance between the Idylla™ KRAS Mutation Assay and the confirmed reference routine test results was found to be 98.9%. The Idylla™ KRAS Mutation Assay enabled detection of 5 additional KRAS-mutated samples not detected previously with reference methods. As conclusion the Idylla™ KRAS Mutation Test can be applied as routine tool in any clinical setting, without needing molecular infrastructure or expertise, to guide the personalized treatment of colorectal cancer patients.
Highlights
The Kirsten rat sarcoma viral oncogene (KRAS) belongs to a family of related RAS genes, comprising three known human isoforms, i.e., KRAS, NRAS, and HRAS [1, 2]
Using the IdyllaTM KRAS Mutation Assay, the KRAS mutational status of 374 archived clinical colorectal cancer formalin-fixed paraffin-embedded (FFPE) samples was tested at 12 centers
Discordant Results: Mutation Detected by Routine Reference Method and Not By IdyllaTM KRAS Mutation Assay In FFPE material of 12 colorectal cancer patients, a mutation in the KRAS oncogene previously detected by a routine reference method was not detected when reanalyzing the clinical archival material with the IdyllaTM KRAS Mutation Assay (Table 5)
Summary
The Kirsten rat sarcoma viral oncogene (KRAS) belongs to a family of related RAS genes, comprising three known human isoforms, i.e., KRAS, NRAS, and HRAS [1, 2]. KRAS encodes the KRAS protein, consisting of 188 or 189 amino acids (depending on exon 4 utilization), which is a small membrane-bound GTPase that plays a pivotal role in cell signal transduction. Ligand binding of a nearby transmembrane tyrosine kinase receptor, like the epidermal growth factor receptor (EGFR), leads to activation of KRAS, which is directly downstream of this receptor. Once in its active state, KRAS in turn activates a wide variety of downstream effectors, influencing cell proliferation and cell survival. Mutated KRAS remains in the active state, leading to a loss of its regulatory function on downstream effectors and eventually to cancer cell survival
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