title: Clustered genomic alterations in chromosome 7p dictate outcomes and targeted treatment responses of lung adenocarcinoma with EGFR-activating mutations.
abstract: OBJECTIVE
  Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been proven more effective for patients with lung adenocarcinoma with EGFR-activating mutation rather than wild type, the former group still includes approximately 30% nonresponders. The molecular basis of this substantial response heterogeneity is unknown. Our purpose was to seek molecular aberrations contributing to disease progression at the genome-wide level and identify the prognostic signature unique to patients with EGFR-activating mutation.
  
  
  METHODS
  We first investigated the molecular differences between tumors with EGFR-activating mutation and wild-type tumors by conducting high-density array comparative genomic hybridization on a collection of 138 adenocarcinoma tissues. We then used an independent group of 114 patients to validate the clinical relevance of copy-number alterations (CNAs) in predicting overall and disease-free survival. Finally, focusing on 23 patients with EGFR mutation receiving EGFR-TKI treatment, we investigated the association between CNAs and response to EGFR-TKIs.
  
  
  RESULTS
  We identified chromosome regions with differential CNAs between tumors with EGFR-activating mutation and wild-type tumors and found the aberration sites to cluster highly on chromosome 7p. A cluster of six representative chromosome 7p genes predicted overall and disease-free survival for patients with EGFR-activating mutation but not for those with wild type. Importantly, simultaneous presence of more genes with increased CNAs in this cluster correlated with less favorable response to EGFR-TKIs in patients with EGFR-activating mutation.
  
  
  CONCLUSIONS
  Our results shed light on why responses to EGFR-TKIs are heterogeneous among patients with EGFR-activating mutation. They may lead to better patient management in this population.
authors.affiliation: National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Shinsheng
authors.initials: S
authors.lastname: Yuan
authors.forename: Sung-Liang
authors.initials: SL
authors.lastname: Yu
authors.forename: Hsuan-Yu
authors.initials: HY
authors.lastname: Chen
authors.forename: Yi-Chiung
authors.initials: YC
authors.lastname: Hsu
authors.forename: Kang-Yi
authors.initials: KY
authors.lastname: Su
authors.forename: Huei-Wen
authors.initials: HW
authors.lastname: Chen
authors.forename: Chih-Yi
authors.initials: CY
authors.lastname: Chen
authors.forename: Chong-Jen
authors.initials: CJ
authors.lastname: Yu
authors.forename: Jin-Yuan
authors.initials: JY
authors.lastname: Shih
authors.forename: Yih-Leong
authors.initials: YL
authors.lastname: Chang
authors.forename: Chiou-Ling
authors.initials: CL
authors.lastname: Cheng
authors.forename: Chung-Ping
authors.initials: CP
authors.lastname: Hsu
authors.forename: Jiun-Yi
authors.initials: JY
authors.lastname: Hsia
authors.forename: Chien-Yu
authors.initials: CY
authors.lastname: Lin
authors.forename: Guani
authors.initials: G
authors.lastname: Wu
authors.forename: Chia-Hsin
authors.initials: CH
authors.lastname: Liu
authors.forename: Chin-Di
authors.initials: CD
authors.lastname: Wang
authors.forename: Kang-Chung
authors.initials: KC
authors.lastname: Yang
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Chen
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Lai
authors.forename: Chu-Chun
authors.initials: CC
authors.lastname: Hsu
authors.forename: Tai-Ching
authors.initials: TC
authors.lastname: Lin
authors.forename: Tsung-Ying
authors.initials: TY
authors.lastname: Yang
authors.forename: Kun-Cheieh
authors.initials: KC
authors.lastname: Chen
authors.forename: Kuo-Hsuan
authors.initials: KH
authors.lastname: Hsu
authors.forename: Jeremy J W
authors.initials: JJ
authors.lastname: Chen
authors.forename: Gee-Chen
authors.initials: GC
authors.lastname: Chang
authors.forename: Ker-Chau
authors.initials: KC
authors.lastname: Li
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics*; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D002869:Chromosome Aberrations; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D018628:Gene Dosage; D015894:Genome, Human; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D015996:Survival Rate
chemical_list: D004273:DNA, Neoplasm; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors