Clinicopathologic features of non-small-cell lung cancer with EML4-ALK fusion gene

Ann Surg Oncol. 2010 Mar;17(3):889-97. doi: 10.1245/s10434-009-0808-7.


Background: A fusion gene between echinoderm microtubule-associated protein-like 4 (EML4) and the anaplastic lymphoma kinase (ALK) has recently been identified in nonsmall-cell lung cancers (NSCLCs). We screened for EML4-ALK fusion genes and examined the clinicopathological and genetic characteristics of fusion-harboring NSCLC tumors.

Methods: We examined 313 NSCLC samples from patients who underwent resection at our hospital between May 2001 and July 2005. We screened for the fusion genes using reverse-transcription polymerase chain reaction (RT-PCR) assay and confirmed the results with direct sequencing. We also examined mutations in the epidermal growth factor receptor (EGFR), KRAS, and ERBB2 genes.

Results: Five EML4-ALK fusion genes were detected (four from 111 female samples and one from 202 male samples; 1.6% overall). All five genes were found in adenocarcinomas and accounted for 2.4% of the 211 adenocarcinoma samples. One EML4-ALK fusion was variant 1, and two were variant 3. In addition, we also found two new fusion variants. Patients with fusion-positive tumors were nonsmokers or light smokers. Among the 211 adenocarcinomas, mutations in EGFR, KRAS, and ERBB2 were detected in 105, 29, and 7 tumors, respectively. Interestingly, all of the fusion-positive NSCLCs had no mutations within these genes.

Conclusions: EML4-ALK fusion genes were observed predominantly in adenocarcinomas, in female or nonsmoking populations. Additionally, the EML4-ALK fusions were mutually exclusive with mutations in the EGFR, KRAS, and ERBB2 genes.

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Aged
  • Carcinoma, Large Cell / genetics
  • Carcinoma, Large Cell / pathology
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology
  • ErbB Receptors / genetics
  • Female
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology*
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Neoplasm Staging
  • Oncogene Proteins, Fusion / genetics*
  • Prognosis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins p21(ras)
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor, ErbB-2 / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • ras Proteins / genetics


  • EML4-ALK fusion protein, human
  • KRAS protein, human
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • EGFR protein, human
  • ERBB2 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins