Causes and consequences of microsatellite instability in endometrial carcinoma.
Causes and consequences of microsatellite instability in endometrial carcinoma.
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发表时间：
1999-01
期刊：
影响因子：
11.2
通讯作者：
C. C. Gurin-C.;M. Federici;Lan Kang;J. Boyd
中科院分区：
文献类型：
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作者：
C. C. Gurin-C.;M. Federici;Lan Kang;J. Boyd
微卫星重复序列的遗传不稳定性[微卫星不稳定性（MI）]常见于与遗传性非息肉病性结直肠癌综合征相关的肿瘤中，是参与DNA错配修复特定途径的几个基因中任何一个失活突变的结果。零星的（即，包括结肠直肠癌、胃癌和子宫内膜癌在内的几种肿瘤类型的（非遗传性的）表现也在很大一部分病例中表现出MI。许多MI+散发性结直肠癌与错配修复基因的体细胞突变相关，并且在这些癌症中，具有编码区微卫星的几个基因经常突变。然而，在散发性子宫内膜癌中MI的分子原因和后果仍然不清楚。本研究的目的是：（a）鉴定一系列散发性子宫内膜癌，明确MI的证据;（B）确定错配修复基因的体细胞改变与MI相关的程度;（c）确定已知在MI+胃肠道癌中被破坏的含有编码区微卫星重复序列的基因是否在MI+子宫内膜癌中也被破坏。采用微卫星标记的共识面板，对来自57例连续子宫内膜癌病例的正常和肿瘤DNA配对进行了MI证据的检查。14例病例（25%）显示明确的MI证据，与先前发表的MI+散发性子宫内膜癌发病率估计值一致。对这些病例进行错配修复基因MSH 2和MLH 1的编码区和外显子-内含子边界的突变筛查。虽然检测到几种多态性，但在这些基因中没有发现明显有害的突变。然而，值得注意的是，在14例MI+病例中的10例（71%）中发现MLH 1启动子区域的超甲基化。TGF β 11 R、IGFI 1 R、BAX、E2 F4、MSH 3、MSH 6、BRCA 1和BRCA 2基因编码区微卫星重复序列的体细胞突变通常很少见。4例MI+肿瘤（29%）在PTEN基因中含有体细胞突变，其中只有1例可能是MI的结果。这些数据表明，已知的错配修复基因的体细胞突变失活并不能解释绝大多数散发性子宫内膜癌伴MI的原因，这些病例中的很大一部分可能与MLH 1启动子的高甲基化有因果关系。此外，在MI+胃肠道癌中经常突变的具有编码区微卫星的基因在MI+子宫内膜癌中很少突变，这意味着在这种肿瘤类型中存在MI致瘤作用的替代分子靶点。
Genetic instability of microsatellite repeat sequences [microsatellite instability (MI)] is commonly seen in tumors associated with the hereditary nonpolyposis colorectal cancer syndrome and is a result of inactivating mutations in any of several genes involved in a particular pathway of DNA mismatch repair. Sporadic (i.e., nonhereditary) manifestations of several tumor types, including colorectal, gastric, and endometrial carcinomas, also exhibit MI in a significant fraction of cases. Many MI+ sporadic colorectal carcinomas are associated with somatic mutations of mismatch repair genes, and several genes with coding region microsatellites are frequently mutated as a result in these cancers. The molecular causes and consequences of MI in sporadic endometrial carcinomas remain obscure, however. The aims of this study were: (a) to identify a series of sporadic endometrial carcinomas with clear evidence of MI; (b) to determine the extent to which somatic alterations in mismatch repair genes are associated with this MI; and (c) to establish whether the genes containing coding region microsatellite repeats that are known to be disrupted in MI+ gastrointestinal cancers are also disrupted in MI+ endometrial carcinomas. Matched pairs of normal and tumor DNA from 57 consecutive cases of endometrial carcinoma were examined for evidence of MI using a consensus panel of microsatellite markers. Fourteen cases (25%) displayed unequivocal evidence of MI, consistent with previously published estimates of the incidence of MI+ sporadic endometrial carcinoma. These cases were subjected to a mutation screen of the coding regions and exon-intron boundaries of the mismatch repair genes MSH2 and MLH1. Although several polymorphisms were detected, no clearly deleterious mutations were found in either of these genes. Notably, however, hypermethylation of the MLH1 promoter region was identified in 10 of 14 (71%) MI+ cases. Somatic mutations in coding region microsatellite repeats in the TGFbetaIIR, IGFIIR, BAX, E2F4, MSH3, MSH6, BRCA1, and BRCA2 genes were generally rare. Four MI+ tumors (29%) contained somatic mutations in the PTEN gene, only one of which was likely the result of MI. These data indicate that somatic mutational inactivation of known mismatch repair genes does not account for the great majority of sporadic endometrial carcinomas with MI and that a significant fraction of these cases may instead be causally associated with hypermethylation of the MLH1 promoter. Furthermore, genes with coding region microsatellites that are frequently mutated in MI+ gastrointestinal cancers are rarely mutated in MI+ endometrial cancers, implying the existence of alternative molecular targets for the tumorigenic effects of MI in this tumor type.