title: Identification of somatic mutations in EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers.
abstract: BACKGROUND
  Lung adenocarcinoma is a highly heterogeneous disease with various etiologies, prognoses, and responses to therapy. Although genome-scale characterization of lung adenocarcinoma has been performed, a comprehensive somatic mutation analysis of EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers has not been conducted.
  
  
  METHODS
  We analyzed whole exome sequencing data from 16 EGFR/KRAS/ALK-negative lung adenocarcinomas and additional 54 tumors in two expansion cohort sets. Candidate loci were validated by target capture and Sanger sequencing. Gene set analysis was performed using Ingenuity Pathway Analysis.
  
  
  RESULTS
  We identified 27 genes potentially implicated in the pathogenesis of lung adenocarcinoma. These included targetable genes involved in PI3K/mTOR signaling (TSC1, PIK3CA, AKT2) and receptor tyrosine kinase signaling (ERBB4) and genes not previously highlighted in lung adenocarcinomas, such as SETD2 and PBRM1 (chromatin remodeling), CHEK2 and CDC27 (cell cycle), CUL3 and SOD2 (oxidative stress), and CSMD3 and TFG (immune response). In the expansion cohort (N = 70), TP53 was the most frequently altered gene (11%), followed by SETD2 (6%), CSMD3 (6%), ERBB2 (6%), and CDH10 (4%). In pathway analysis, the majority of altered genes were involved in cell cycle/DNA repair (P <0.001) and cAMP-dependent protein kinase signaling (P <0.001).
  
  
  CONCLUSIONS
  The genomic makeup of EGFR/KRAS/ALK-negative lung adenocarcinomas in never-smokers is remarkably diverse. Genes involved in cell cycle regulation/DNA repair are implicated in tumorigenesis and represent potential therapeutic targets.
authors.affiliation: Department of Chemistry, Yonsei University, Seoul 120-752, Korea.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Ahn
authors.affiliation: Department of Pharmacology, Pharmacogenomic Research Center for Membrane Transporters, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752, Korea ; Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Han Sang
authors.initials: HS
authors.lastname: Kim
authors.affiliation: College of Medicine, Seoul National University, Seoul 110-799, Korea ; Hwasung Public Health Center, Hwasung, Korea.
authors.forename: Jung-Ki
authors.initials: JK
authors.lastname: Yoon
authors.affiliation: Department of Chemistry, Yonsei University, Seoul 120-752, Korea.
authors.forename: Hoon
authors.initials: H
authors.lastname: Jang
authors.affiliation: Department of Pharmacology, Pharmacogenomic Research Center for Membrane Transporters, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Soo Min
authors.initials: SM
authors.lastname: Han
authors.affiliation: Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Sungho
authors.initials: S
authors.lastname: Eun
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Hyo Sup
authors.initials: HS
authors.lastname: Shim
authors.affiliation: JE UK Institute for Cancer Research, Gumi City, Kyungbuk, Korea.
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Dae Joon
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jin Gu
authors.initials: JG
authors.lastname: Lee
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Chang Young
authors.initials: CY
authors.lastname: Lee
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Mi Kyung
authors.initials: MK
authors.lastname: Bae
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Kyung Young
authors.initials: KY
authors.lastname: Chung
authors.affiliation: Division of Pulmonology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Ji Ye
authors.initials: JY
authors.lastname: Jung
authors.affiliation: Division of Pulmonology, 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: Division of Pulmonology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Se Kyu
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Division of Pulmonology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Joon
authors.initials: J
authors.lastname: Chang
authors.affiliation: Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Hye Ryun
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Joo Hang
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Pharmacogenomic Research Center for Membrane Transporters, Brain Korea 21 PLUS Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
authors.affiliation: Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea ; JE UK Institute for Cancer Research, Gumi City, Kyungbuk, Korea.
authors.forename: Byoung Chul
authors.initials: BC
authors.lastname: Cho
authors.affiliation: Department of Oral Biology, College of Dentistry, Yonsei University, Seoul, Republic of Korea.
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Yonsei University, Seoul 120-752, Korea.
authors.forename: Duhee
authors.initials: D
authors.lastname: Bang