Gene expression profiling of microsatellite unstable and microsatellite stable endometrial cancers indicates distinct pathways of aberrant signaling
Gene expression profiling of microsatellite unstable and microsatellite stable endometrial cancers indicates distinct pathways of aberrant signaling
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DOI：
10.1158/0008-5472.can-04-0850
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发表时间：
2005-06-15
期刊：
影响因子：
11.2
通讯作者：
Barrett, JC
中科院分区：
文献类型：
--
作者：
Risinger, JI;Maxwell, GL;Barrett, JC
微卫星不稳定性（NISI）是一种分子表型，存在于25%的子宫内膜癌中。我们研究了具有和不具有MSI表型的早期子宫内膜样癌的全局基因表达谱，以检验MSI表型可能决定其他相似癌症之间的独特分子特征的假设。来自这些病例的表达数据的无监督主成分分析表明基于MSI表型的两种不同的癌症分组。在这些癌症中，相对少量的具有高统计值（P < 0.001）的阵列特征（392）被鉴定为驱动不稳定性特征;这些转录物中的109个差异至少2倍。这些数据确定了MSI和微卫星稳定（MSS）癌症的不同基因表达谱，这表明MSI癌症的发展部分是通过与类似稳定癌症不同的机制实现的。特别是，我们发现的证据表明，分泌型卷曲相关蛋白家族的两个成员（SFRP 1和SFRP 4）更频繁地下调MSI癌症相比，MSS癌症。下调伴随着SFRP 1启动子的高甲基化。SFRP 1在12个MSI癌症中的8个中高甲基化，而在16个MSS癌症中仅3个中甲基化。发现WNT靶向成纤维细胞生长因子18在MSI癌症中上调。这些数据将组织学相似的子宫内膜样子宫内膜癌分为两个不同的组，这影响了治疗和预防。
Microsatellite instability (NISI) is a molecular phenotype present in similar to 25% of endometrial cancers. We examined the global gene expression profiles of early-stage endometrioid endometrial cancers with and without the MSI phenotype to test the hypothesis that MSI phenotype may determine a unique molecular signature among otherwise similar cancers. Unsupervised principal component analysis of the expression data from these cases indicated two distinct groupings of cancers based on MSI phenotype. A relatively small number of array features (392) at high statistical value (P < 0.001) were identified that drive the instability signature in these cancers; 109 of these transcripts differed by at least 2-fold. These data identify distinct gene expression profiles for MSI and micro-satellite stable (MSS) cancers, which suggest that cancers with MSI develop in part by different mechanisms from their similar stable counterparts. In particular, we found evidence that two members of the secreted frizzled related protein family (SFRP1 and SFRP4) were more frequently down-regulated in MSI cancers as compared with MSS cancers. Down-regulation was accompanied by promoter hypermethylation for SFRP1. SFRP1 was hypermethylated in 8 of 12 MSI cancers whereas only 3 of 16 MSS cancers were methylated. The WNT target fibroblast growth factor 18 was found to be up-regulated in MSI cancers. These data classify histologically similar endometrioid endometrial cancers into two distinct groupings with implications affecting therapy and prevention.