Jonkers Y M H, Claessen S M H, Feuth T, van Kessel A Geurts, Ramaekers F C S, Veltman J A, Speel E-J M
Department of Molecular Cell Biology, Research Institute Growth and Development (GROW), University of Maastricht, The Netherlands.
J Pathol. 2006 Dec;210(4):450-8. doi: 10.1002/path.2072.
Insulinomas represent the predominant syndromic subtype of endocrine pancreatic tumours. Previous molecular studies have shown that gain of chromosome 9q rather than MEN1 gene mutation is an important early event in tumour development and that chromosomal instability is associated with metastatic disease. In order to identify new gene loci and to define further the critical genetic events in insulinoma tumourigenesis, 27 insulinomas were investigated by array-based comparative genomic hybridization (array CGH) on 3.7 k genomic BAC arrays (resolution < or =1 Mb). Fluorescence in situ hybridization was used to validate alterations in a subset of tumours. Array CGH most frequently detected loss of chromosomes 11q and 22q and gains of chromosome 9q. The chromosomal regions of interest (CRI) included 11q24.1 (56%), 22q13.1 (67%), 22q13.31 (56%), and 9q32 (63%). Evaluation of the simultaneous occurrence of these aberrations in the individual tumours revealed that gain of 9q32 and loss of 22q13.1 are early genetic events in insulinomas, occurring independently of the other alterations. In tumours with increased genomic complexity, these alterations were often detected simultaneously, occurring in the same tumour cells. Losses of 11q24.1 and 22q13.31 were also associated with these more advanced tumour cases. The CRIs identified most likely harbour crucial candidate genes important in insulinoma tumourigenesis.
胰岛素瘤是胰腺内分泌肿瘤中主要的综合征亚型。既往分子研究表明，9号染色体长臂的获得而非MEN1基因突变是肿瘤发生过程中的重要早期事件，且染色体不稳定性与转移性疾病相关。为了鉴定新的基因位点并进一步明确胰岛素瘤发生过程中的关键遗传事件，我们利用基于3.7k基因组BAC阵列（分辨率≤1Mb）的阵列比较基因组杂交（array CGH）技术对27例胰岛素瘤进行了研究。荧光原位杂交用于验证部分肿瘤中的改变。Array CGH最常检测到11号染色体长臂和22号染色体长臂的缺失以及9号染色体长臂的获得。感兴趣的染色体区域（CRI）包括11q24.1（56%）、22q13.1（67%）、22q13.31（56%）和9q32（63%）。对这些畸变在单个肿瘤中同时出现情况的评估显示，9q32的获得和22q13.1的缺失是胰岛素瘤的早期遗传事件，其发生独立于其他改变。在基因组复杂性增加的肿瘤中，这些改变常同时被检测到，出现在同一肿瘤细胞中。11q24.1和22q13.31的缺失也与这些更晚期的肿瘤病例相关。所鉴定的CRI很可能包含在胰岛素瘤发生过程中重要的关键候选基因。
