Identification of somatic mutations in EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers

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• 作者：Jin Woo Ahn (1)
  Han Sang Kim (2) (3)
  Jung-Ki Yoon (4) (5)
  Hoon Jang (1)
  Soo Min Han (2)
  Sungho Eun (6)
  Hyo Sup Shim (7)
  Hyun-Jung Kim (8)
  Dae Joon Kim (9)
  Jin Gu Lee (9)
  Chang Young Lee (9)
  Mi Kyung Bae (9)
  Kyung Young Chung (9)
  Ji Ye Jung (10)
  Eun Young Kim (10)
  Se Kyu Kim (10)
  Joon Chang (10)
  Hye Ryun Kim (3)
  Joo Hang Kim (3)
  Min Goo Lee (2)
  Byoung Chul Cho (3) (8)
  Ji Hyun Lee (11)
  Duhee Bang (1)
  
• 刊名：Genome Medicine
• 出版年：2014
• 出版时间：February 2014
• 年：2014
• 卷：6
• 期：2
• 全文大小：865 KB
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• 作者单位：Jin Woo Ahn (1)
  Han Sang Kim (2) (3)
  Jung-Ki Yoon (4) (5)
  Hoon Jang (1)
  Soo Min Han (2)
  Sungho Eun (6)
  Hyo Sup Shim (7)
  Hyun-Jung Kim (8)
  Dae Joon Kim (9)
  Jin Gu Lee (9)
  Chang Young Lee (9)
  Mi Kyung Bae (9)
  Kyung Young Chung (9)
  Ji Ye Jung (10)
  Eun Young Kim (10)
  Se Kyu Kim (10)
  Joon Chang (10)
  Hye Ryun Kim (3)
  Joo Hang Kim (3)
  Min Goo Lee (2)
  Byoung Chul Cho (3) (8)
  Ji Hyun Lee (11)
  Duhee Bang (1)
  
  1. Department of Chemistry, Yonsei University, Seoul, 120-752, Korea
  2. 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
  3. Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 120-752, Korea
  4. College of Medicine, Seoul National University, Seoul, 110-799, Korea
  5. Hwasung Public Health Center, Hwasung, Korea
  6. Yonsei University College of Medicine, Seoul, 120-752, Korea
  7. Department of Pathology, Yonsei University College of Medicine, Seoul, 120-752, Korea
  8. JE UK Institute for Cancer Research, Gumi City, Kyungbuk, Korea
  9. Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea
  10. Division of Pulmonology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
  11. Department of Oral Biology, College of Dentistry, Yonsei University, Seoul, Republic of Korea
  
• ISSN：1756-994X

文摘

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--0), 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.