Common Pathogenetic Mechanism Involving Human Chromosome 18 in Familial and Sporadic Ileal Carcinoid Tumors
Common Pathogenetic Mechanism Involving Human Chromosome 18 in Familial and Sporadic Ileal Carcinoid Tumors
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DOI：
10.1002/gcc.20834
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发表时间：
2011-02-01
影响因子：
3.7
通讯作者：
Janson, Eva T.
中科院分区：
文献类型：
--
作者：
Cunningham, Janet L.;de Stahl, Teresita Diaz;Janson, Eva T.
产生5-羟色胺的小肠内分泌癌（回肠类癌）是一种临床上独特的内分泌肿瘤。它通常被认为是一种散发性疾病，其分子病因学知之甚少。我们报告了55例散发性和家族性诊断为这种疾病的患者的综合临床和分子研究。建立了9个家系，包括23名受影响的受试者，符合常染色体显性遗传方式。家族性和散发性患者表现出难以区分的临床图片。来自45个个体的61个肿瘤的分子分析，包括8个家族性和37个散发性患者，目的是使用BAC和Illumina SNP阵列和基因表达谱通过Affyphin芯片确定全局拷贝数畸变。在散发性和家族性肿瘤中均发现了18号染色体畸变;分别为100%和38%。其他不太常见的畸变在两组中也很常见。总体表达谱显示无差异表达基因。当比较患者匹配的原发肿瘤和转移瘤时，仅在转移瘤中观察到7号染色体的频繁获得。值得注意的是，后者畸变与实体生长模式形态学相关（P < 0.01），这是一种先前与预后不良相关的组织病理学特征。散发性和家族性病例之间的临床和分子相似性表明肿瘤发生涉及共同的发病机制。回肠类癌的家族性变异是一种以前未被认识的常染色体显性遗传性肿瘤疾病，我们建议称之为家族性回肠内分泌癌（FIEC）。我们的研究结果表明，FIEC肿瘤抑制基因的位置接近端粒的18 q，参与发展的遗传性和散发性肿瘤。(C)2010 Wiley-Liss，Inc.
Serotonin producing endocrine carcinoma of small intestine (ileal carcinoid) is a clinically distinct endocrine tumor. It is generally considered as a sporadic disease and its molecular etiology is poorly understood. We report comprehensive clinical and molecular studies of 55 sporadic and familial patients diagnosed with this condition. Nine pedigrees encompassing 23 affected subjects were established, consistent with autosomal dominant mode of inheritance. Familial and sporadic patients demonstrated indistinguishable clinical pictures. Molecular analyses of 61 tumors from 45 individuals, including eight familial and 37 sporadic patients, aimed at determination of global copy number aberrations using BAC and Illumina SNP arrays and gene expression profiling by Affymetrix chips. Chromosome 18 aberrations were identified in both sporadic and in familial tumors; 100% vs. 38%, respectively. Other, less frequent aberrations were also common for both groups. Global expression profiles revealed no differentially expressed genes. Frequent gain of chromosome 7 was exclusively observed in metastases, when patient matched primary tumors and metastases were compared. Notably, the latter aberration correlated with solid growth pattern morphology (P < 0.01), a histopathological feature that has previously been related to worse prognosis. The clinical and molecular similarities identified between sporadic and familial cases suggest a common pathogenetic mechanism involved in tumor initiation. The familial variant of ileal carcinoid represents a previously unrecognized autosomal dominant inherited tumor disease, which we propose to call Familial Ileal Endocrine Carcinoma (FIEC). Our findings indicate the location of a FIEC tumor suppressor gene near the telomere of 18q, involved in development of inherited and sporadic tumors. (C) 2010 Wiley-Liss, Inc.