Differential gene expression profiling of matched primary renal cell carcinoma and metastases reveals upregulation of extracellular matrix genes
Differential gene expression profiling of matched primary renal cell carcinoma and metastases reveals upregulation of extracellular matrix genes
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DOI：
10.1093/annonc/mdw652
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发表时间：
2017-03-01
影响因子：
50.5
通讯作者：
Eckel-Passow, J. E.
中科院分区：
文献类型：
--
作者：
Ho, T. H.;Serie, D. J.;Eckel-Passow, J. E.
背景资料：大多数肾细胞癌（RCC）研究分析原发性肿瘤，相应的结果外推到转移性RCC肿瘤。然而，目前尚不清楚原发性RCC肿瘤的基因表达谱是否与患者匹配的转移性肿瘤不同。因此，我们试图确定患者匹配的原发性和转移性RCC肿瘤之间的差异表达基因，以了解RCC metastases.Patients和方法的发展的分子机制：我们比较了患者匹配的原发性和转移性RCC肿瘤之间的基因表达谱使用两个阶段的设计。首先，我们在15对原发性RCC [14例透明细胞RCC（ccRCC），1例乳头状]肿瘤和患者匹配的肺转移瘤上使用了Affyellow微阵列。其次，我们使用定制的NanoString面板在114名ccRCC患者的独立队列中验证了7个候选基因。使用混合效应线性模型评估差异基因表达;包括表示患者的随机效应以解释配对数据。第三，使用癌症基因组图谱（TCGA）数据评估原发性ccRCC肿瘤中无转移和总生存率的相关性。结果：我们鉴定并验证了7个功能性参与细胞外基质（ECM）形成的基因的上调：DCN，SLIT 2，LUM，LAMA 2，ADAMTS 12，CEACAM 6和LMO 3。在原发性ccRCC中，CEACAM 6和LUM与无转移和总生存率显著相关（P < 0.01）。结论：我们使用迄今为止最大的一组，据我们所知，患者匹配的原发性和转移性ccRCC肿瘤的基因表达谱进行评估，并确定了转移中ECM基因的上调。我们的研究暗示ECM基因的上调是导致ccRCC中内脏、骨和软组织转移的关键分子事件。
Background: The majority of renal cell carcinoma (RCC) studies analyze primary tumors, and the corresponding results are extrapolated to metastatic RCC tumors. However, it is unknown if gene expression profiles from primary RCC tumors differs from patient-matched metastatic tumors. Thus, we sought to identify differentially expressed genes between patient-matched primary and metastatic RCC tumors in order to understand the molecular mechanisms underlying the development of RCC metastases.Patients and methods: We compared gene expression profiles between patient-matched primary and metastatic RCC tumors using a two-stage design. First, we used Affymetrix microarrays on 15 pairs of primary RCC [14 clear cell RCC (ccRCC), 1 papillary] tumors and patient-matched pulmonary metastases. Second, we used a custom NanoString panel to validate seven candidate genes in an independent cohort of 114 ccRCC patients. Differential gene expression was evaluated using a mixed effect linear model; a random effect denoting patient was included to account for the paired data. Third, The Cancer Genome Atlas (TCGA) data were used to evaluate associations with metastasis-free and overall survival in primary ccRCC tumors.Results: We identified and validated up regulation of seven genes functionally involved in the formation of the extracellular matrix (ECM): DCN, SLIT2, LUM, LAMA2, ADAMTS12, CEACAM6 and LMO3. In primary ccRCC, CEACAM6 and LUM were significantly associated with metastasis-free and overall survival (P < 0.01).Conclusions: We evaluated gene expression profiles using the largest set to date, to our knowledge, of patient-matched primary and metastatic ccRCC tumors and identified up regulation of ECM genes in metastases. Our study implicates up regulation of ECM genes as a critical molecular event leading to visceral, bone and soft tissue metastases in ccRCC.