Department of Pulmonary Diseases, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, IARC-WHO, Lyon, France.
J Thorac Oncol. 2018 Jun;13(6):752-766. doi: 10.1016/j.jtho.2018.02.002. Epub 2018 Feb 14.
Carcinoids and large cell neuroendocrine carcinomas (LCNECs) are rare neuroendocrine lung tumors. Here we provide an overview of the most updated data on the molecular characteristics of these diseases. Recent genomic studies showed that carcinoids generally contain a low mutational burden and few recurrently mutated genes. Most of the reported mutations occur in chromatin-remodeling genes (e.g., menin 1 gene [MEN1]), and few affect genes of the phosphoinositide 3-kinase (PI3K)-AKT-mechanistic target of rapamycin gene pathway. Aggressive disease has been related to chromothripsis, DNA-repair gene mutations, loss of orthopedia homeobox/CD44, and upregulation of ret proto-oncogene gene (RET) gene expression. In the case of LCNECs, which present with a high mutation burden, two major molecular subtypes have been identified: one with biallelic inactivation of tumor protein p53 gene (TP53) and retinoblastoma gene (RB1), a hallmark of SCLC; and the other one with biallelic inactivation of TP53 and serine/threonine kinase 11 gene (STK11)/kelch like ECH associated protein 1 gene (KEAP1), genes that are frequently mutated in NSCLC. These data, together with the identification of common mutations in the different components of combined LCNEC tumors, provide further evidence of the close molecular relation of LCNEC with other lung tumor types. In terms of therapeutic options, future studies should explore the association between mechanistic target of rapamycin pathway mutations and response to mechanistic target of rapamycin inhibitors in carcinoids. For LCNEC, preliminary data suggest that the two molecular subtypes might have a predictive value for chemotherapy response, but this observation needs to be validated in randomized prospective clinical trials. Finally, delta like Notch canonical ligand 3 inhibitors and immunotherapy may provide alternative options for patient-tailored therapy in LCNEC.
类癌和大细胞神经内分泌癌（LCNEC）是罕见的神经内分泌肺肿瘤。在此，我们对这些疾病的分子特征的最新数据进行了综述。最近的基因组研究表明，类癌通常含有较低的突变负担和少数反复突变的基因。大多数报道的突变发生在染色质重塑基因（如 MEN1 基因）中，而很少影响磷酸肌醇 3-激酶（PI3K）-AKT-雷帕霉素靶蛋白基因途径的基因。侵袭性疾病与染色体重排、DNA 修复基因突变、同源盒转录因子 CD44 缺失和 RET 原癌基因表达上调有关。在 LCNEC 中，存在高突变负担，已确定两种主要的分子亚型：一种是抑癌基因 TP53 和视网膜母细胞瘤基因（RB1）的双等位基因失活，这是小细胞肺癌的标志；另一种是抑癌基因 TP53 和丝氨酸/苏氨酸激酶 11 基因（STK11）/Kelch 样 ECH 相关蛋白 1 基因（KEAP1）的双等位基因失活，这些基因在非小细胞肺癌中经常发生突变。这些数据，加上在联合 LCNEC 肿瘤的不同成分中鉴定出的常见突变，进一步证明了 LCNEC 与其他肺癌类型在分子上密切相关。在治疗选择方面，未来的研究应探讨雷帕霉素靶蛋白途径突变与雷帕霉素靶蛋白抑制剂在类癌中的反应之间的关系。对于 LCNEC，初步数据表明，这两种分子亚型可能对化疗反应具有预测价值，但这一观察结果需要在随机前瞻性临床试验中得到验证。最后，Delta 样 Notch 经典配体 3 抑制剂和免疫疗法可能为 LCNEC 的个体化治疗提供替代选择。
