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Compound EGFR mutation is frequently detected with co-mutations of actionable genes and associated with poor clinical outcome in lung adenocarcinoma

 Eun Young Kim  ;  Eun Na Cho  ;  Heae Surng Park  ;  Ji Young Hong  ;  Seri Lim  ;  Jong Pil Youn  ;  Seung Yong Hwang  ;  Yoon Soo Chang 
 Cancer Biology & Therapy, Vol.17(3) : 237-245, 2016 
Journal Title
 Cancer Biology & Therapy 
Issue Date
Adenocarcinoma/drug therapy ; Adenocarcinoma/enzymology ; Adenocarcinoma/genetics* ; Adenocarcinoma/surgery ; Adult ; Aged ; Chemotherapy, Adjuvant ; Disease-Free Survival ; Female ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/enzymology ; Lung Neoplasms/genetics* ; Lung Neoplasms/surgery ; Male ; Middle Aged ; Mutation, Missense* ; Receptor, Epidermal Growth Factor/antagonists & inhibitors ; Receptor, Epidermal Growth Factor/genetics* ; Survival Rate
Compound EGFR mutation ; EGFR ; NGS ; co-mutation ; lung adenocarcinoma ; repeated deep sequencing ; simple EGFR mutation
Compound EGFR mutations, defined as double or multiple mutations in the EGFR tyrosine kinase domain, are frequently detected with advances in sequencing technology but its clinical significance is unclear. This study analyzed 61 cases of EGFR mutation positive lung adenocarcinoma using next-generation sequencing (NGS) based repeated deep sequencing panel of 16 genes that contain actionable mutations and investigated clinical implication of compound EGFR mutations. Compound EGFR mutation was detected in 15 (24.6%) of 61 cases of EGFR mutation-positive lung adenocarcinoma. The majority (12/15) of compound mutations are combination of the atypical mutation and typical mutations such as exon19 deletion, L858R or G719X substitutions, or exon 20 insertion whereas 3 were combinations of rare atypical mutations. The patients with compound mutation showed shorter overall survival than those with simple mutations (83.7 vs. 72.8 mo; P = 0.020, Breslow test). Among the 115 missense mutations discovered in the tested genes, a few number of actionable mutations were detected irrelevant to the subtype of EGFR mutations, including ALK rearrangement, BCL2L11 intron 2 deletion, KRAS c.35G>A, PIK3CA c.1633G>A which are possible target of crizotinib, BH3 mimetics, MEK inhibitors, and PI3K-tyrosine kinase inhibitors, respectively. 31 missense mutations were detected in the cases with simple mutations whereas 84 in those with compound mutation, showing that the cases with compound missense mutation have higher burden of missense mutations (P = 0.001, independent sample t-test). Compound EGFR mutations are detected at a high frequency using NGS-based repeated deep sequencing. Because patients with compound EGFR mutations showed poor clinical outcomes, they should be closely monitored during follow-up.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
김은영(Kim, Eun Young) ORCID logo https://orcid.org/0000-0002-3281-5744
박혜성(Park, Heae Surng)
장윤수(Chang, Yoon Soo) ORCID logo https://orcid.org/0000-0003-3340-4223
조은나(Cho, Eun Na)
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