Clinical significance of EML4-ALK fusion gene and association with EGFR and KRAS gene mutations in 208 Chinese patients with non-small cell lung cancer

PLoS One. 2013;8(1):e52093. doi: 10.1371/journal.pone.0052093. Epub 2013 Jan 14.

Abstract

The EML4-ALK fusion gene has been recently identified in a small subset of non-small cell lung cancer (NSCLC) patients who respond positively to ALK inhibitors. The characteristics of the EML4-ALK fusion gene in Chinese patients with NSCLC are poorly understood. Here, we report on the prevalence of EML4-ALK, EGFR status and KRAS mutations in 208 Chinese patients with NSCLC. EGFR mutations were found in 24.5% (51/208) of patients. In concordance with previous reports, these mutations were identified at high frequencies in females (47.5% vs 15.0% in males; P<0.05); never-smokers (42.3% vs 13.9% in smokers; P<0.05), and adenocarcinoma patients (44.2% vs 8.0% in non-adenocarcinoma patients; P<0.05). There were only 2.88% (6/208) patients with KRAS mutations in our study group. We identified 7 patients who harbored the EML4-ALK fusion gene (3.37%, 7/208), including 4 cases with variant 3 (57.1%), 2 with variant 1, and 1 with variant 2. All positive cases corresponded to female patients (11.5%, 7/61). Six of the positive cases were non-smokers (7.69%, 6/78). The incidence of EML4-ALK translocation in female, non-smoking adenocarcinoma patients was as high as 15.2% (5/33). No EGFR/KRAS mutations were detected among the EML4-ALK positive patients. Pathological analysis showed no difference between solid signet-ring cell pattern (4/7) and mucinous cribriform pattern (3/7) in ALK-positive patients. Immunostaining showed intratumor heterogeneity of ALK rearrangement in primary carcinomas and 50% (3/6) of metastatic tumors with ALK-negative staining. Meta-analysis demonstrated that EML4-ALK translocation occurred in 4.84% (125/2580) of unselected patients with NSCLC, and was also predominant in non-smoking patients with adenocarcinoma. Taken together, EML4-ALK translocations were infrequent in the entire NSCLC patient population, but were frequent in the NSCLC subgroup of female, non-smoker, adenocarcinoma patients. There was intratumor heterogeneity of ALK rearrangement in primary carcinomas and at metastatic sites.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Asian Continental Ancestry Group / genetics*
  • Base Sequence
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • China
  • ErbB Receptors / genetics*
  • Female
  • Fluorescent Antibody Technique
  • Genetic Association Studies*
  • Genetic Predisposition to Disease
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Male
  • Meta-Analysis as Topic
  • Middle Aged
  • Molecular Sequence Data
  • Mutation / genetics*
  • Oncogene Proteins, Fusion / genetics*
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins p21(ras)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Survival Analysis
  • Translocation, Genetic
  • ras Proteins / genetics*

Substances

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

Grant support

This research is supported partially by grants from the National Natural Science Foundation of China (81172233), the Science and Technology Support Key Program of Tianjin (09ZCZDSF04000, 09ZCZDSF03800), the Tianjin Natural Science Foundation (12JCZDJC24400), the project of the Ministry of Education for New Century Excellent Talents (NCET-10-0956), and the Wujieping Foundation (320.6720.10007, 320.6740.10008, 3206720.10008). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.