Comparative profiling of primary colorectal carcinomas and liver metastases identifies LEF1 as a prognostic biomarker.
Comparative profiling of primary colorectal carcinomas and liver metastases identifies LEF1 as a prognostic biomarker.
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DOI：
10.1371/journal.pone.0016636
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发表时间：
2011-02-24
期刊：
影响因子：
3.7
通讯作者：
Pollack JR
中科院分区：
文献类型：
--
作者：
Lin AY;Chua MS;Choi YL;Yeh W;Kim YH;Azzi R;Adams GA;Sainani K;van de Rijn M;So SK;Pollack JR
我们试图确定有临床意义的基因来预测生存率和结直肠癌肝转移(CLM)的风险，CLM是结直肠癌(CRC)最常见的转移部位。我们分析了31例原发结直肠癌和32例不匹配的慢性粒细胞白血病的基因表达谱，并进行了基因芯片的显著性分析(SAM)以确定这两组之间的差异表达基因。为了确定两个排名较高的差异表达基因的临床相关性，我们用组织芯片(TMA)分析了分泌型磷蛋白1(SPP1或骨桥蛋白)和淋巴增强因子1(LEF1)的表达，该组织芯片代表了154名原发结直肠癌患者的独立集合。使用SAM的监督分析发现，与原发结直肠癌相比，963个基因在CLM中的表达显著增加，错误发现率为0.5%。TMA分析显示SPP1和LEF1蛋白在60%和44%的结直肠癌中过度表达。慢性淋巴细胞性白血病的发生与LEF1的过度表达显著相关(卡方p = 0.042)，而与spp1的过度表达无关(p = 0.14)。Kaplan Meier分析显示，LEF1过表达患者的存活率显著降低(p<0.01)，但spp1基因过表达患者的存活率无显著差异(p = 0.11)。单变量和多变量分析均确定分期(p<；0.0001)和LEF1过度表达(p<；0.05)是重要的预后标志，但与肿瘤分级或spp1无关。在慢性结直肠癌和原发结直肠癌之间差异表达的基因中，我们证明LEF1在原发结直肠癌中的过度表达是生存不良和增加肝转移风险的预后因素。
We sought to identify genes of clinical significance to predict survival and the risk for colorectal liver metastasis (CLM), the most common site of metastasis from colorectal cancer (CRC). We profiled gene expression in 31 specimens from primary CRC and 32 unmatched specimens of CLM, and performed Significance Analysis of Microarrays (SAM) to identify genes differentially expressed between these two groups. To characterize the clinical relevance of two highly-ranked differentially-expressed genes, we analyzed the expression of secreted phosphoprotein 1 (SPP1 or osteopontin) and lymphoid enhancer factor-1 (LEF1) by immunohistochemistry using a tissue microarray (TMA) representing an independent set of 154 patients with primary CRC. Supervised analysis using SAM identified 963 genes with significantly higher expression in CLM compared to primary CRC, with a false discovery rate of <0.5%. TMA analysis showed SPP1 and LEF1 protein overexpression in 60% and 44% of CRC cases, respectively. Subsequent occurrence of CLM was significantly correlated with the overexpression of LEF1 (chi-square p = 0.042), but not SPP1 (p = 0.14). Kaplan Meier analysis revealed significantly worse survival in patients with overexpression of LEF1 (p<0.01), but not SPP1 (p = 0.11). Both univariate and multivariate analyses identified stage (p<0.0001) and LEF1 overexpression (p<0.05) as important prognostic markers, but not tumor grade or SPP1. Among genes differentially expressed between CLM and primary CRC, we demonstrate overexpression of LEF1 in primary CRC to be a prognostic factor for poor survival and increased risk for liver metastasis.
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