Mutational analysis of pulmonary tumours with neuroendocrine features using targeted massive parallel sequencing: a comparison of a neglected tumour group.
Mutational analysis of pulmonary tumours with neuroendocrine features using targeted massive parallel sequencing: a comparison of a neglected tumour group.
复制标题
DOI：
10.1038/bjc.2015.397
复制
发表时间：
2015-12-22
影响因子：
8.8
通讯作者：
Mairinger FD
中科院分区：
文献类型：
--
作者：
Vollbrecht C;Werner R;Walter RF;Christoph DC;Heukamp LC;Peifer M;Hirsch B;Burbat L;Mairinger T;Schmid KW;Wohlschlaeger J;Mairinger FD
肺癌是全球癌症相关死亡的主要原因。典型和非典型类癌（TC和AC），大细胞神经内分泌癌（LCNEC）和小细胞肺癌（SCLC）是显示神经内分泌分化的肺肿瘤亚组。随着分子病理学在常规诊断中的影响越来越大，人们对可靠的生物标志物的兴趣也越来越大，这些生物标志物可以帮助区分这些亚组，并可以对患者进行更个性化的治疗。70例福尔马林固定、石蜡包埋（FFPE）肺神经内分泌肿瘤（17例TC、17例AC、19例LCNEC和17例SCLC）的集合用于通过高通量测序鉴定生物标志物。使用MiSeq仪器上的Illumina TruSeq Amplicon-Cancer Panel，筛选样品中48个肿瘤相关基因的221个突变热点的改变。在应用严格的算法过滤了>26 000个检测到的变异后，在29个基因和49名患者中共发现了130个突变。JAK 3、NRAS、RB 1和VHL 1的突变仅在SCLC中发现，而FGFR 2突变仅在LCNEC中检测到。KIT、PTEN、HNF 1A和SMO在AC中改变。SMAD 4突变对应TC亚型。我们证明了突变的频率随着肿瘤类型的恶性程度而增加。有趣的是，五分之四的ATM突变患者显示TP 53的额外改变，这是迄今为止最常见的改变基因（130人中有28人; 22%）。我们发现ATM-（P=0.022; P=0.008）和TP 53突变患者（P<0.001）的肿瘤类型和IASLC分级之间存在相关性。两个突变基因均与淋巴结浸润和远处转移有关（P <0.005）。此外，患有高级别肿瘤的PIK 3CA突变患者显示出总生存期降低（P=0.040），并且高级别神经内分泌肺癌患者中APC和ATM的突变频率与无进展生存期（PFS）相关（P=0.020）。实施高通量测序分析的神经内分泌肺肿瘤已经表明，即使这些肿瘤包括几个亚型不同的临床侵略性，他们共享一些分子特征。对神经内分泌肿瘤生物学的进一步了解将为临床管理提供新方法的机会，从而更好地预测预后和治疗反应。
Lung cancer is the leading cause of cancer-related deaths worldwide. The typical and atypical carcinoid (TC and AC), the large-cell neuroendocrine carcinoma (LCNEC) and the small-cell lung cancers (SCLC) are subgroups of pulmonary tumours that show neuroendocrine differentiations. With the rising impact of molecular pathology in routine diagnostics the interest for reliable biomarkers, which can help to differentiate these subgroups and may enable a more personalised treatment of patients, grows. A collective of 70 formalin-fixed, paraffin-embedded (FFPE) pulmonary neuroendocrine tumours (17 TCs, 17 ACs, 19 LCNECs and 17 SCLCs) was used to identify biomarkers by high-throughput sequencing. Using the Illumina TruSeq Amplicon-Cancer Panel on the MiSeq instrument, the samples were screened for alterations in 221 mutation hot spots of 48 tumour-relevant genes. After filtering >26 000 detected variants by applying strict algorithms, a total of 130 mutations were found in 29 genes and 49 patients. Mutations in JAK3, NRAS, RB1 and VHL1 were exclusively found in SCLCs, whereas the FGFR2 mutation was detected in LCNEC only. KIT, PTEN, HNF1A and SMO were altered in ACs. The SMAD4 mutation corresponded to the TC subtype. We prove that the frequency of mutations increased with the malignancy of tumour type. Interestingly, four out of five ATM-mutated patients showed an additional alteration in TP53, which was by far the most frequently altered gene (28 out of 130; 22%). We found correlations between tumour type and IASLC grade for ATM- (P=0.022; P=0.008) and TP53-mutated patients (P<0.001). Both mutated genes were also associated with lymph node invasion and distant metastasis (P⩽0.005). Furthermore, PIK3CA-mutated patients with high-grade tumours showed a reduced overall survival (P=0.040) and the mutation frequency of APC and ATM in high-grade neuroendocrine lung cancer patients was associated with progression-free survival (PFS) (P=0.020). The implementation of high-throughput sequencing for the analysis of the neuroendocrine lung tumours has revealed that, even if these tumours encompass several subtypes with varying clinical aggressiveness, they share a number of molecular features. An improved understanding of the biology of neuroendocrine tumours will offer the opportunity for novel approaches in clinical management, resulting in a better prognosis and prediction of therapeutic response.