The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS

Authors

  • Daisy Wing-Sze Wong BSc,

    1. Department of Pathology, University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China
    Search for more papers by this author
  • Elaine Lai-Han Leung PhD,

    1. Department of Pathology, University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China
    Search for more papers by this author
  • Kimpton Kam-Ting So BSc,

    1. Department of Pathology, University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China
    Search for more papers by this author
  • Issan Yee-San Tam PhD,

    1. Department of Pathology, University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China
    Search for more papers by this author
  • Alan Dart-Loon Sihoe MBBS,

    1. Cardiothoracic Surgery Unit, Grantham Hospital, Hong Kong Special Administrative Region, China
    Search for more papers by this author
  • Lik-Cheung Cheng MBBS,

    1. Cardiothoracic Surgery Unit, Grantham Hospital, Hong Kong Special Administrative Region, China
    Search for more papers by this author
  • Kwok-Keung Ho MBBS,

    1. Cardiothoracic Surgery Unit, Queen Elizabeth Hospital, Hong Kong Special Administrative Region, China
    Search for more papers by this author
  • Joseph Siu-Kie Au MBBS, MSc,

    1. Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong Special Administrative Region, China
    Search for more papers by this author
  • Lap-Ping Chung DPhil,

    1. Department of Pathology, University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China
    Search for more papers by this author
  • Maria Pik Wong MD,

    Corresponding author
    1. Department of Pathology, University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China
    • Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong SAR, China
    Search for more papers by this author
    • Fax: (011) 852-2872-5197

  • University of Hong Kong Lung Cancer Study Group

    Search for more papers by this author
    • Members of the University of Hong Kong Lung Cancer Study Group include Lik-Cheung Cheng, Daniel Tsin-Tien Chua, Lap-Ping Chung, James Chung-Man Ho, Elaine Lai-Han Leung, Alan Dart-Loon Sihoe, Vicky Pui-Chi Tin, and Maria Pik Wong.


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. Cancer 2009. © 2009 American Cancer Society.

Ancillary