title: Compound EGFR mutation is frequently detected with co-mutations of actionable genes and associated with poor clinical outcome in lung adenocarcinoma.
abstract: 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.
authors.affiliation: a Department of Internal Medicine , Yonsei University College of Medicine , Seoul , Republic of Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Kim
authors.affiliation: a Department of Internal Medicine , Yonsei University College of Medicine , Seoul , Republic of Korea.
authors.forename: Eun Na
authors.initials: EN
authors.lastname: Cho
authors.affiliation: b Pathology, Yonsei University College of Medicine , Seoul , Republic of Korea.
authors.forename: Heae Surng
authors.initials: HS
authors.lastname: Park
authors.affiliation: c Department of Bio-Nanotechnology , Hanyang University , Sangnok-gu, Ansan , Gyeonggi-do , Republic of Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Hong
authors.forename: Seri
authors.initials: S
authors.lastname: Lim
authors.forename: Jong Pil
authors.initials: JP
authors.lastname: Youn
authors.affiliation: c Department of Bio-Nanotechnology , Hanyang University , Sangnok-gu, Ansan , Gyeonggi-do , Republic of Korea.
authors.forename: Seung Yong
authors.initials: SY
authors.lastname: Hwang
authors.affiliation: a Department of Internal Medicine , Yonsei University College of Medicine , Seoul , Republic of Korea.
authors.forename: Yoon Soo
authors.initials: YS
authors.lastname: Chang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000601:surgery; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D015996:Survival Rate
chemical_list: C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Compound EGFR mutation; EGFR; NGS; co-mutation; lung adenocarcinoma; repeated deep sequencing; simple EGFR mutation