Frequent mutations in the neurotrophic tyrosine receptor kinase, gene family in large cell neuroendocrine carcinoma of the lung
Frequent mutations in the neurotrophic tyrosine receptor kinase, gene family in large cell neuroendocrine carcinoma of the lung
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DOI：
10.1002/humu.20707
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发表时间：
2008-05-01
期刊：
影响因子：
3.9
通讯作者：
Buttitta, Fianuna
中科院分区：
文献类型：
--
作者：
Marchetti, Antonio;Felicioni, Lara;Buttitta, Fianuna
神经营养酪氨酸受体激酶(NTRK)家族可能与多种肿瘤的发生和发展有关，包括肺癌。我们研究了大量肺神经内分泌肿瘤(PNETs)和无神经内分泌分化的非小细胞肺癌(NSCLC)的NTRK基因家族突变。应用单链构象多态(SSCP)技术和NTRK1、NTRK2、NTRK3酪氨酸激酶结构域(TKD)序列分析方法，对538例肺癌组织中NTRK1、NTRK2、NTRK3酪氨酸激酶结构域(TKD)进行分析，其中典型类癌17例，非典型类癌10例，小细胞肺癌39例，大细胞神经内分泌癌29例，非小细胞肺癌443例。从未发现NTRK1基因发生突变。在NTRK2和NTRK3中共检测到10个体细胞突变，主要位于激活和催化环。在95例PNET中有9例(10%)发现NTRK突变，但在调查的443例非小细胞肺癌中0例发现NTRK突变。未观察到TCS、ACS和SCLC的突变。有趣的是，所有突变都局限于LCNEC组织类型，占病例的31%。显微切割LCNECs并腺癌(ADC)后进行的突变分析显示，只有神经内分泌区呈阳性，提示NTRK突变参与了LCNECs神经内分泌成分的发生。我们的数据表明，NTRK基因TKD的体细胞突变在LCNEC中很常见。这种突变事件可能代表着这些肿瘤的癌变过程中的重要一步，并可能对选择靶向治疗的患者具有潜在的意义。
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.