Pancreatic insulinomas in multiple endocrine neoplasia, type I knockout mice can develop in the absence of chromosome instability or microsatellite instability.
Pancreatic insulinomas in multiple endocrine neoplasia, type I knockout mice can develop in the absence of chromosome instability or microsatellite instability.
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多发性内分泌肿瘤中的胰腺胰岛素瘤，I型基因敲除小鼠可以在没有染色体不稳定或微卫星不稳定的情况下发生。
DOI：
10.1158/0008-5472.can-04-1648
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发表时间：
2004
期刊：
影响因子：
11.2
通讯作者：
Collins,FrancisS
中科院分区：
文献类型：
--
作者：
Scacheri,PeterC;Kennedy,AlyssaL;Chin,Koei;Miller,MeghanT;Hodgson,JGraeme;Gray,JoeW;Marx,StephenJ;Spiegel,AllenM;Collins,FrancisS
I 型多发性内分泌肿瘤 (MEN1) 是一种遗传性癌症综合征，其特征是肿瘤主要发生在内分泌组织中。负责的基因充当肿瘤抑制因子，受影响的杂合个体中的肿瘤在野生型等位基因失活后发生。先前的研究表明，Men1 基因敲除小鼠会出现多种胰腺胰岛素瘤，但这种情况是在 Men1 基因的两个拷贝均丢失数月后发生的。这些研究表明，Men1 的缺失并不足以形成肿瘤，额外的体细胞遗传变化很可能是肿瘤发生所必需的。通常的预期是，此类突变可能是由染色体不稳定或微卫星不稳定机制引起的。在对十多个此类肿瘤的研究中，使用基于阵列的比较基因组杂交、荧光原位杂交、使用跨基因组的多个微卫星标记进行杂合性丢失分析以及实时 PCR 来评估 DNA 拷贝数等技术，发现许多成熟的克隆性腺瘤仍然是显着的整倍体。此外，杂合Men1小鼠中野生型Men1等位基因的丢失是由于整个带有突变体的染色体的丢失和重复而发生的。因此，在 MEN1 小鼠模型中，被假定导致肿瘤发生的体细胞遗传变化必须异常微妙，要么发生在核苷酸水平上，要么通过表观遗传机制发生。
Multiple endocrine neoplasia, type I (MEN1) is an inherited cancer syndrome characterized by tumors arising primarily in endocrine tissues. The responsible gene acts as a tumor suppressor, and tumors in affected heterozygous individuals occur after inactivation of the wild-type allele. Previous studies have shown thatMen1knockout mice develop multiple pancreatic insulinomas, but this occurs many months after loss of both copies of theMen1gene. These studies imply that loss ofMen1is not alone sufficient for tumor formation and that additional somatic genetic changes are most likely essential for tumorigenesis. The usual expectation is that such mutations would arise either by a chromosomal instability or microsatellite instability mechanism. In a study of more then a dozen such tumors, using the techniques of array-based comparative genomic hybridization, fluorescentin situhybridization, loss of heterozygosity analysis using multiple microsatellite markers across the genome, and real time PCR to assess DNA copy number, it appears that many of these full-blown clonal adenomas remain remarkably euploid. Furthermore, the loss of the wild-typeMen1allele in heterozygousMen1mice occurs by loss and reduplication of the entire mutant-bearing chromosome. Thus, the somatic genetic changes that are postulated to lead to tumorigenesis in a mouse model of MEN1 must be unusually subtle, occurring at either the nucleotide level or through epigenetic mechanisms.