title: EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset.
abstract: A subset of lung cancers harbors a small inversion within chromosome 2p, giving rise to a transforming fusion gene, EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene), which encodes an activated tyrosine kinase. We have earlier examined the presence of EML4-ALK by multiplex reverse transcription-polymerase chain reaction in 363 specimens of lung cancer, identifying 11 adenocarcinoma cases featuring the fusion gene. In this study, we clinicopathologically examined the characteristics of the EML4-ALK-positive cases, including the mutation status of EGFR, KRAS, and TP53, and whether they were of thyroid transcription factor-1 (TTF-1) cell lineage or not. Of 11 patients, 4 (36%) with EML4-ALK-positive lung adenocarcinomas who were below 50 years of age were affected by these diseases, as compared with 12 of 242 patients (5.0%) with EML4-ALK-negative lung adenocarcinomas (P=0.00038). EML4-ALK-positive lung adenocarcinomas were characterized by less-differentiated grade (P=0.0082) and acinar-predominant structure (P<0.0001) in histology. Furthermore, the presence of EML4-ALK appears to be mutually exclusive for EGFR and KRAS mutations (P=0.00018), whereas coexisting with TP53 mutations at a low frequency (1/11=9.1%), and correlating with non- or light smoking (P=0.040), in line with the TTF-1 immunoreactivity. Thus, EML4-ALK-positive tumors may form a distinct entity among lung adenocarcinomas, characterized by young onset, acinar histology, no or rare mutations in EGFR, KRAS, and TP53, and a TTF-1 cell lineage, all in agreement with the prevalence in non- or light smokers.
authors.affiliation: Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Inamura
authors.forename: Kengo
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Togashi
authors.forename: Satoko
authors.initials: S
authors.lastname: Hatano
authors.forename: Hironori
authors.initials: H
authors.lastname: Ninomiya
authors.forename: Noriko
authors.initials: N
authors.lastname: Motoi
authors.forename: Ming-yon
authors.initials: MY
authors.lastname: Mun
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Sakao
authors.forename: Sakae
authors.initials: S
authors.lastname: Okumura
authors.forename: Ken
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Manabu
authors.initials: M
authors.lastname: Soda
authors.forename: Young Lim
authors.initials: YL
authors.lastname: Choi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mano
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ishikawa
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D017668:Age of Onset; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018773:Genes, erbB-1; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C522504:EML4-ALK fusion protein, human; C117307:KRAS protein, human; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; C504003:TTF1 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins