Marchetti Antonio, Felicioni Lara, Pelosi Giuseppe, Del Grammastro Maela, Fumagalli Caterina, Sciarrotta Mariagrazia, Malatesta Sara, Chella Antonio, Barassi Fabio, Mucilli Felice, Camplese Pierpaolo, D'Antuono Tommaso, Sacco Rocco, Buttitta Fiamma
Clinical Research Center, Center of Excellence on Aging, University-Foundation, Chieti, Italy.
Hum Mutat. 2008 May;29(5):609-16. doi: 10.1002/humu.20707.
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.
神经营养性酪氨酸受体激酶（NTRK）家族可能与包括肺癌在内的多种肿瘤性疾病的发生和进展有关。我们对大量无神经内分泌分化形态学证据的肺神经内分泌肿瘤（PNET）和非小细胞肺癌（NSCLC）进行了研究，以检测NTRK基因家族的突变情况。通过单链构象多态性（SSCP）以及对NTRK1、NTRK2和NTRK3酪氨酸激酶结构域（TKD）进行测序，对总共538例原发性肺癌进行了评估，其中包括17例典型类癌（TC）、10例非典型类癌（AC）、39例小细胞肺癌（SCLC）、29例大细胞神经内分泌癌（LCNEC）和443例NSCLC。从未发现NTRK1基因发生突变。在NTRK2和NTRK3中总共检测到10个体细胞突变，大部分位于激活环和催化环。在95例PNET中有9例（10%）发现了NTRK突变，但在研究的443例NSCLC中未发现NTRK突变。在TC、AC和SCLC中未观察到突变。有趣的是，所有突变均局限于LCNEC组织学类型，在该类型中突变病例占31%。对LCNEC与腺癌（ADC）混合样本进行显微切割后进行的突变分析表明，只有神经内分泌区域呈阳性，这表明NTRK突变参与了混合性LCNEC神经内分泌成分的发生。我们的数据表明，NTRK基因TKD中的体细胞突变在LCNEC中很常见。此类突变事件可能是这些肿瘤发生过程中的重要一步，并且可能对靶向治疗患者的选择具有潜在意义。
