In silico ascription of gene expression differences to tumor and stromal cells in a model to study impact on breast cancer outcome.
In silico ascription of gene expression differences to tumor and stromal cells in a model to study impact on breast cancer outcome.
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DOI：
10.1371/journal.pone.0014002
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发表时间：
2010-11-19
期刊：
影响因子：
3.7
通讯作者：
Sørlie T
中科院分区：
文献类型：
--
作者：
Myhre S;Mohammed H;Tramm T;Alsner J;Finak G;Park M;Overgaard J;Børresen-Dale AL;Frigessi A;Sørlie T
乳腺肿瘤由几种不同的组织成分组成。尽管存在异质性，但大多数基因表达分析传统上都是在没有事先对组织样本进行显微解剖的情况下进行的。因此，获得的基因表达谱反映了不同组织成分对mRNA的贡献。我们利用组织病理学对198个新鲜冷冻的乳腺肿瘤组织样本的肿瘤面积和间质组织成分进行了与远处转移相关的细胞类型相关基因表达分析。通过将每个肿瘤的贡献与各自肿瘤标本中间质和肿瘤上皮细胞的相对含量进行权衡，在发生远处转移的患者和没有发生远处转移的患者的肿瘤中识别出差异表达的基因探针集。这些分析是在不同的假设下进行的，与间质细胞相比，肿瘤上皮细胞的mRNA转录水平。一组30个差异表达的基因探针被单独归因于癌细胞。此外，两组38个差异表达基因探针和5个差异表达基因探针主要分别与肿瘤上皮细胞和基质细胞相关。最后，一组26个差异表达的基因探针被鉴定出来，与细胞类型无关。这些差异表达的基因在一组激光捕获显微解剖的浸润性导管癌的独立基因表达数据中得到验证。我们提出了一种方法，利用病理信息和加权t-统计量来识别和归因于肿瘤上皮和/或基质细胞的差异表达基因。虽然在对实体瘤进行的基因芯片实验中可以检测到基质细胞部分的转录贡献，但远处转移组和无远处转移组之间的基因表达差异主要归因于原发乳腺肿瘤的肿瘤上皮细胞。而PIP5K2A基因在远处转移组间质细胞中的表达显著高于无远处转移组。这些发现在来自显微解剖的乳腺组织代表性隔室的基因表达数据中得到了证实。所描述的方法也被发现对不同的组织病理学程序是健壮的。
Breast tumors consist of several different tissue components. Despite the heterogeneity, most gene expression analyses have traditionally been performed without prior microdissection of the tissue sample. Thus, the gene expression profiles obtained reflect the mRNA contribution from the various tissue components. We utilized histopathological estimations of area fractions of tumor and stromal tissue components in 198 fresh-frozen breast tumor tissue samples for a cell type-associated gene expression analysis associated with distant metastasis. Sets of differentially expressed gene-probes were identified in tumors from patients who developed distant metastasis compared with those who did not, by weighing the contribution from each tumor with the relative content of stromal and tumor epithelial cells in their individual tumor specimen. The analyses were performed under various assumptions of mRNA transcription level from tumor epithelial cells compared with stromal cells. A set of 30 differentially expressed gene-probes was ascribed solely to carcinoma cells. Furthermore, two sets of 38 and five differentially expressed gene-probes were mostly associated to tumor epithelial and stromal cells, respectively. Finally, a set of 26 differentially expressed gene-probes was identified independently of cell type focus. The differentially expressed genes were validated in independent gene expression data from a set of laser capture microdissected invasive ductal carcinomas. We present a method for identifying and ascribing differentially expressed genes to tumor epithelial and/or stromal cells, by utilizing pathologic information and weighted t-statistics. Although a transcriptional contribution from the stromal cell fraction is detectable in microarray experiments performed on bulk tumor, the gene expression differences between the distant metastasis and no distant metastasis group were mostly ascribed to the tumor epithelial cells of the primary breast tumors. However, the gene PIP5K2A was found significantly elevated in stroma cells in distant metastasis group, compared to stroma in no distant metastasis group. These findings were confirmed in gene expression data from the representative compartments from microdissected breast tissue. The method described was also found to be robust to different histopathological procedures.
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影响因子：
3.2
作者：
Blake，CA;Brown，LM;Helmke，SM
通讯作者：
Helmke，SM
DOI：
10.1006/bbrc.1995.2876
发表时间：
1995-12-26
影响因子：
3.1
作者：
Sakaguchi, G;Orita, S;Takai, Y
通讯作者：
Takai, Y
DOI：
10.1073/pnas.2536479100
发表时间：
2004-01-13
影响因子：
11.1
作者：
Stuart, RO;Wachsman, W;Mercola, D
通讯作者：
Mercola, D
影响因子：
3
作者：
Noth, S;Benecke, A
通讯作者：
Benecke, A
DOI：
10.1186/bcr1506
发表时间：
2006
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Cleator SJ;Powles TJ;Dexter T;Fulford L;Mackay A;Smith IE;Valgeirsson H;Ashworth A;Dowsett M
通讯作者：
Dowsett M