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Abstract
Mutational profiling is recommended for selecting targeted therapy and predicting
prognosis of metastatic colorectal cancer (CRC). Detection of coexisting mutations
within the same pathway, which are usually mutually exclusive, raises the concern
for potential laboratory errors. In this retrospective study for quality assessment
of a next-generation sequencing assay, we examined BRAF, KRAS, and NRAS genes within
the mitogen-activated protein kinase (MAPK) pathway and the PIK3CA gene within the
phosphatidylinositol 3-kinase (mTOR) pathway in 744 CRC specimens submitted to our
clinical diagnostics laboratory. Although coexistence of mutations between the MAPK
and mTOR pathways was observed, it rarely occurred within the MAPK pathway. Retrospective
quality assessments identified false detection of coexisting activating KRAS and NRAS
mutations in 1 specimen and confirmed 2 activating KRAS mutations in 2 specimens and
coexisting activating KRAS and NRAS mutations in 2 specimens, but no coexisting activating
RAS and BRAF mutations. There were 15 CRCs with a kinase-impaired BRAF mutation, including
3 with a coexisting activating KRAS mutation, which may have therapeutic implications.
Multiregional analysis based on different histologic features demonstrated that coexisting
KRAS and NRAS mutations may be present in the same or different tumor populations
and showed that invasion of adenomas by synchronous adenocarcinomas of different clonal
origin may result in detection of coexisting mutations within the MAPK pathway. In
this study, we proposed an operating procedure for clinical validation of unexpected
coexisting mutations. Further studies are warranted to elucidate the biological significance
and clinical implications of coexisting mutations within the MAPK pathway.