title: The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS.
abstract: BACKGROUND
  The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene resulting from the chromosome inversion inv(2)(p21;p23) recently was identified in nonsmall cell lung cancer (NSCLC). The authors of this study investigated the frequency, genetic and clinicopathologic profiles of EML4-ALK in Chinese patients with NSCLC.
  
  
  METHODS
  EML4-ALK was investigated in 266 resected primary NSCLC, including adenocarcinomas (AD), lymphoepithelioma-like carcinomas, squamous cell carcinomas, mucoepidermoid carcinomas, and adenosquamous carcinomas, by reverse transcriptase-polymerase chain reaction and was verified by sequencing. EML4-ALK protein expression was studied by immunohistochemistry.
  
  
  RESULTS
  Thirteen tumors (4.9%) had EML4-ALK comprising 4 fusion transcript variants with fusion of the variable segments from 5' EML4 to 3' ALK and with preservation of the ALK kinase domain. The most common variant consisted of 8 tumors with variant 3 that involved EML4 exon 6. The others included 2 tumors with variant 1 (exon 13), 2 tumors with variant 2 (exon 20), and 1 tumor with the novel variant 5 (exon 18). There were 11 ADs and 2 unusual carcinomas with mixed squamous and glandular components. Immunohistochemistry demonstrated diffuse ALK fusion proteins in the tumor cell cytoplasm. EML4-ALK was associated with nonsmokers (P = .009). Tumors with the fusion gene had the wild-type epidermal growth factor receptor (EGFR) (P = .001) and v-Ki-ras2/Kirsten rat sarcoma viral oncogene homolog (KRAS) genes. Patients who had EML4-ALK-positive AD had a younger median age (P = .018) compared with patients who did not have the fusion gene.
  
  
  CONCLUSIONS
  The EML4-ALK fusion gene was present in various histologic types of NSCLC. It occurred in mutual exclusion to EGFR and KRAS mutations and was associated with nonsmokers. The authors concluded that EML4-ALK may be useful for predicting the potential response to ALK inhibitors as a therapeutic option for patients with lung cancer.
authors.affiliation: Department of Pathology, University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China.
authors.forename: Daisy Wing-Sze
authors.initials: DW
authors.lastname: Wong
authors.forename: Elaine Lai-Han
authors.initials: EL
authors.lastname: Leung
authors.forename: Kimpton Kam-Ting
authors.initials: KK
authors.lastname: So
authors.forename: Issan Yee-San
authors.initials: IY
authors.lastname: Tam
authors.forename: Alan Dart-Loon
authors.initials: AD
authors.lastname: Sihoe
authors.forename: Lik-Cheung
authors.initials: LC
authors.lastname: Cheng
authors.forename: Kwok-Keung
authors.initials: KK
authors.lastname: Ho
authors.forename: Joseph Siu-Kie
authors.initials: JS
authors.lastname: Au
authors.forename: Lap-Ping
authors.initials: LP
authors.lastname: Chung
authors.forename: Maria
authors.initials: M
authors.lastname: Pik Wong
mesh_terms: D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D019457:Chromosome Breakage; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D012907:Smoking
chemical_list: C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; D066246:ErbB Receptors