Nikiforova M N, Nikiforov Y E, Biddinger P, Gnepp D R, Grosembacher L A, Wajchenberg B L, Fagin J A, Cohen R M
Division of Endocrinology/Metabolism, Department of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267-0547, USA.
Clin Endocrinol (Oxf). 1999 Jul;51(1):27-33. doi: 10.1046/j.1365-2265.1999.00785.x.
Pancreatic islet betacell tumours occur either sporadically or as part of inherited neoplastic syndromes, most commonly multiple endocrine neoplasia (MEN) type 1. Recently, a transgenic mouse model has been established in which the expression of the SV40 large T antigen was targeted to betacells by the rat insulin promoter, leading to the development of multiple pancreatic betacell tumours. In the advanced stages of tumour evolution, these tumours exhibited a high prevalence of loss of heterozygosity (LOH) on mouse chromosomes 9 and 16, at regions syntenic with regions 3q, 3p21, 6q12, 15q24 and 22q of the human genome.
Loss of heterozygosity in human islet cell tumours was analysed in a PCR based approach at regions of the human genome syntenic with the mouse loci linked to pancreatic betacell tumours as well as the MEN1 gene on chromosome 11q13. These included 35 microsatellite markers in the human chromosomal regions 3q, 3p21, 6q12, 11q13, 15q24 and 22q.
21 patients diagnosed with insulinoma were analysed. Histologically, 16 tumours were benign, while 5 were malignant insulinomas.
Thirteen of 21 (62%) tumours were found to have loss of genetic material on chromosome 3. The shortest region of overlap implicated a deletion at 3p14.2-3p21 region, corresponding to the marker D3S1295. We did not detect a substantial frequency of LOH in the other syntenic regions, except for the region of MEN 1 gene on 11q13 found to be deleted in 6 (29%) cases, including 3 of 4 tumours from MEN 1 families. Deletions of 3p14. 2-3p21 were observed in 8 of 15 (53%) benign tumours, and in 5 of 6 (83%) malignant neoplasms.
These results indicate the high frequency of 3p14.2-3p21 deletions in human pancreatic betacell neoplasms. These finding suggest the presence of a tumour suppressor gene in this region, that may be important in the microevolution of these tumours towards malignancy.
胰岛β细胞瘤可散发性发生，或作为遗传性肿瘤综合征的一部分出现，最常见的是1型多发性内分泌肿瘤（MEN）。最近，已建立了一种转基因小鼠模型，其中SV40大T抗原的表达通过大鼠胰岛素启动子靶向β细胞，导致多发性胰岛β细胞瘤的发生。在肿瘤进展的晚期，这些肿瘤在小鼠9号和16号染色体上杂合性缺失（LOH）的发生率很高，这些区域与人类基因组的3q、3p21、6q12、15q24和22q区域同源。
采用基于聚合酶链反应（PCR）的方法，分析人类胰岛细胞瘤在与小鼠胰岛β细胞瘤相关位点以及11号染色体11q13上的MEN1基因同源的人类基因组区域的杂合性缺失情况。这些区域包括人类染色体3q、3p21、6q12、11q13、15q24和22q中的35个微卫星标记。
对21例诊断为胰岛素瘤的患者进行分析。组织学检查显示，16例肿瘤为良性，5例为恶性胰岛素瘤。
21例肿瘤中有13例（62%）在3号染色体上发现有遗传物质缺失。最短的重叠区域涉及3p14.2 - 3p21区域的缺失，对应标记为D3S1295。除了在11q13上的MEN1基因区域，我们在其他同源区域未检测到明显的LOH频率，该区域在6例（29%）病例中被发现缺失，包括来自MEN1家族的4例肿瘤中的3例。15例良性肿瘤中有8例（53%）观察到3p14.2 - 3p21缺失，6例恶性肿瘤中有5例（83%）观察到该缺失。
这些结果表明人类胰岛β细胞瘤中3p14.2 - 3p21缺失的频率很高。这些发现提示该区域存在一个肿瘤抑制基因，这可能在这些肿瘤向恶性发展的微进化过程中起重要作用。
