Abstract:
BACKGROUND:β3-αC loop is a highly conserved structural domain across oncogene families, which is a switch for kinase activity. There have been numerous researches on mutations within β3-αC loop in EGFR, but relatively less in ERBB2, BRAF, and MAP2K1. In addition, previous studies mainly focus on β3-αC deletion in EGFR, which is the most common type affecting kinase activity and driving lung cancer. Other mutation types are not well studied. METHODS:Here we analyzed the profile of β3-αC loop mutations in a total of 10,000 tumor biopsy and/or ctDNA patient samples using hybridization capture-based next-generation sequencing. RESULTS:We identified 1616 mutations within β3-αC loop in this cohort. Most mutations were located in EGFR, with less percentage in ERBB2, BRAF, and MAP2K1. EGFR β3-αC deletions occurred at a high percentage of 96.7% and were all drug-relevant. We also detected rare EGFR β3-αC insertions and point mutations, most of which were related to EGFR TKIs resistance. ERBB2 β3-αC deletions were only found in breast cancers and sensitive to EGFR/ERBB2 inhibitor. Moreover, BRAF and MAP2K1 mutations within β3-αC loop also demonstrated drugs relevance. CONCLUSION:Our study showed that oncogenic mutations within the β3-αC loop of ERBB2, MAP2K1, and BRAF are analogous to that of EGFR, which have profound effect on drug response. Understanding the mutation profile within the β3-αC loop is critical for targeted therapies.
journal_name
Mol Genet Genomic Medjournal_title
Molecular genetics & genomic medicineauthors
Zhang B,Chen Y,Dai P,Yu H,Ma J,Chen C,Zhang Y,Guan Y,Chen R,Liu T,Wang J,Yang L,Yi X,Xia X,Ma Hdoi
10.1002/mgg3.1395subject
Has Abstractpub_date
2020-10-01 00:00:00pages
e1395issue
10issn
2324-9269journal_volume
8pub_type
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journal_title:Molecular genetics & genomic medicine
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