title: Frequent mutations in the neurotrophic tyrosine receptor kinase gene family in large cell neuroendocrine carcinoma of the lung.
abstract: The neurotrophic tyrosine receptor kinase (NTRK) family is potentially implicated in tumorigenesis and progression of several neoplastic diseases, including lung cancer. We investigated a large number of pulmonary neuroendocrine tumors (PNETs) and non-small cell lung carcinomas (NSCLCs) without morphological evidence of neuroendocrine differentiation for mutations in the NTRK gene family. A total of 538 primary lung carcinomas, including 17 typical carcinoids (TCs), 10 atypical carcinoids (ACs), 39 small cell lung carcinomas (SCLCs), 29 large cell neuroendocrine carcinomas (LCNECs), and 443 NSCLCs were evaluated by single-strand conformation polymorphism (SSCP) and sequencing of the tyrosine kinase domain (TKD) of NTRK1, NTRK2, and NTRK3. The NTRK1 gene was never found to be mutated. A total of 10 somatic mutations were detected in NTRK2 and NTRK3, mostly located in the activating and catalytic loops. NTRK mutations were seen in 9 (10%) out of 95 PNETs but in 0 out of 443 NSCLCs investigated. No mutations were observed in TCs, ACs, and SCLCs. Interestingly, all the mutations were restricted to the LCNEC histotype, in which they accounted for 31% of cases. A mutational analysis, performed after microdissection of LCNECs combined with adenocarcinoma (ADC), showed that only neuroendocrine areas were positive, suggesting that NTRK mutations are involved in the genesis of the neuroendocrine component of combined LCNECs. Our data indicate that somatic mutations in the TKD of NTRK genes are frequent in LCNECs. Such mutational events could represent an important step in the cancerogenesis of these tumors and may have potential implications for the selection of patients for targeted therapy.
authors.affiliation: Clinical Research Center, Center of Excellence on Aging, University-Foundation, Chieti, Italy. amarchetti@unich.it
authors.forename: Antonio
authors.initials: A
authors.lastname: Marchetti
authors.forename: Lara
authors.initials: L
authors.lastname: Felicioni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pelosi
authors.forename: Maela
authors.initials: M
authors.lastname: Del Grammastro
authors.forename: Caterina
authors.initials: C
authors.lastname: Fumagalli
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Sciarrotta
authors.forename: Sara
authors.initials: S
authors.lastname: Malatesta
authors.forename: Antonio
authors.initials: A
authors.lastname: Chella
authors.forename: Fabio
authors.initials: F
authors.lastname: Barassi
authors.forename: Felice
authors.initials: F
authors.lastname: Mucilli
authors.forename: Pierpaolo
authors.initials: P
authors.lastname: Camplese
authors.forename: Tommaso
authors.initials: T
authors.lastname: D'Antuono
authors.forename: Rocco
authors.initials: R
authors.lastname: Sacco
authors.forename: Fiamma
authors.initials: F
authors.lastname: Buttitta
mesh_terms: D000595:Amino Acid Sequence; D016022:Case-Control Studies; D020134:Catalytic Domain; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D018358:Neuroendocrine Tumors / Q000201:enzymology / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
chemical_list: D020794:Receptor Protein-Tyrosine Kinases