Principal Component Analysis, Hierarchical Clustering, and Decision Tree Assessment of Plasma mRNA and Hormone Levels as an Early Detection Strategy for Small Intestinal Neuroendocrine (Carcinoid) Tumors
Principal Component Analysis, Hierarchical Clustering, and Decision Tree Assessment of Plasma mRNA and Hormone Levels as an Early Detection Strategy for Small Intestinal Neuroendocrine (Carcinoid) Tumors
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DOI：
10.1245/s10434-008-0251-1
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发表时间：
2009-02-01
影响因子：
3.7
通讯作者：
Kidd, Mark
中科院分区：
文献类型：
--
作者：
Modlin, Irvin M.;Gustafsson, Bjorn I.;Kidd, Mark
神经内分泌肿瘤（NETs）的发病率正在增加（约6%/年），但临床表现不特异性，导致诊断延迟（5-7年；约70%发生转移）。这反映了缺乏敏感的血浆标志物。本研究的目的是探讨单独检测循环信使RNA （mRNA）或联合循环NET相关激素和生长因子是否可以检测胃肠道NET疾病。采用小肠（SI） NET细胞系krj - 1测定实时聚合酶链反应（PCR）检测血液中mRNA的敏感性。从1个krj -1细胞/ml血液中鉴定出NSE、Tph-1和VMAT(2)转录本。从SI-NETs （n = 12）、胃NETs （n = 7）和健康对照（n = 9）的组织和血浆中分离mRNA，并进行实时PCR。Tph-1是SI-NETs的特异性标记物（58%,p < 0.03），而CgA转录本不能区分肿瘤与对照。转移性肿瘤患者比局部肿瘤患者表达更多的标志物转录物（75%对18%，p < 0.02）。检测血浆5-羟色胺（5-HT）、嗜色粒蛋白A （CgA）、胃饥饿素（ghrelin）和结缔组织生长因子（CTGF）片段，结合mRNA水平，并使用决策树建立NET诊断的预测数学模型。SI-NETs和胃NETs诊断的敏感性和特异性分别为81.2%和100%，71.4%和55.6%。我们的结论是，从一个NET细胞/ml血液中可以检测到mRNA。循环血浆Tph-1是SI-NET疾病的一个有希望的标记基因（特异性100%），而标记转录物（bbb2）数量的增加与疾病传播相关。将net相关循环激素和生长因子纳入算法，将SI-NETs的检测灵敏度从58%提高到82%。
Incidence of neuroendocrine tumors (NETs) is increasing (approximately 6%/year), but clinical presentation is nonspecific, resulting in delays in diagnosis (5-7 years; approximately 70% have metastases). This reflects absence of a sensitive plasma marker. The aim of this study is to investigate whether detection of circulating messenger RNA (mRNA) alone or in combination with circulating NET-related hormones and growth factors can detect gastrointestinal NET disease. The small intestinal (SI) NET cell line KRJ-I was used to define the sensitivity of real-time polymerase chain reaction (PCR) for mRNA detection in blood. NSE, Tph-1, and VMAT (2) transcripts were identified from one KRJ-I cell/ml blood. mRNA from the tissue and plasma of SI-NETs (n = 12) and gastric NETs (n = 7), and plasma from healthy controls (n = 9) was isolated and real-time PCR performed. Tph-1 was a specific marker of SI-NETs (58%, p < 0.03) whereas CgA transcripts did not differentiate tumors from controls. Patients with metastatic disease expressed more marker transcripts than localized tumors (75% versus 18%, p < 0.02). Plasma 5-hydroxytryptamine (5-HT), chromogranin A (CgA), ghrelin, and connective tissue growth factor (CTGF) fragments were measured, combined with mRNA levels, and a predictive mathematical model for NET diagnosis developed using decision trees. The sensitivity and specificity to diagnose SI-NETs and gastric NETs were 81.2% and 100%, and 71.4% and 55.6%, respectively. We conclude that mRNA from one NET cell/ml blood can be detected. Circulating plasma Tph-1 is a promising marker gene for SI-NET disease (specificity 100%) while an increased number of marker transcripts (> 2) correlated with disease spread. Including NET-related circulating hormones and growth factors in the algorithm increased the sensitivity of detection of SI-NETs from 58 to 82%.