Discovery of molecular subtypes in leiomyosarcoma through integrative molecular profiling.
Discovery of molecular subtypes in leiomyosarcoma through integrative molecular profiling.
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DOI：
10.1038/onc.2009.381
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发表时间：
2010-02-11
期刊：
影响因子：
8
通讯作者：
van de Rijn, M.
中科院分区：
文献类型：
--
作者：
Beck, A. H.;Lee, C-H;Witten, D. M.;Gleason, B. C.;Edris, B.;Espinosa, I.;Zhu, S.;Li, R.;Montgomery, K. D.;Marinelli, R. J.;Tibshirani, R.;Hastie, T.;Jablons, D. M.;Rubin, B. P.;Fletcher, C. D.;West, R. B.;van de Rijn, M.
关键词：
平滑肌肉瘤(LMS)是一种具有明显形态和分子异质性的软组织肿瘤。我们采用综合分子图谱来发现和表征LMS的分子亚型。对51例LMS患者进行了基因表达谱分析。非监督聚类展示了3个可重复的LMS聚类。对20例LMS样本进行了阵列比较基因组杂交(ACGH)，结果表明，由基因表达决定的分子亚型具有明显的基因组变化。“肌肉富集型”肿瘤的拷贝数变化显著增加(p=0.04)。大多数肌肉丰富的病例表现为16q24缺失，其中含有FANCA，已知在DNA修复中起重要作用；1p36缺失，含有PRDM16，其缺失促进肌肉分化。在LMS组织芯片上对5种高水平表达的标记蛋白(ACTG2、CASQ2、SLMAP、CFL2、Mylk)进行免疫组织化学染色，结果显示这5种蛋白的表达显著相关(均为配对p<；0.005)。在多变量COX回归分析(p<；0.04)中，这5个标记物的表达与疾病特异性生存(DSS)的改善有关。在这项结合了基因表达谱、aCGH和免疫组织化学的分析中，我们确定了不同的分子LMS亚型，为其发病机制提供了洞察力，并确定了预后生物标志物。
Leiomyosarcoma (LMS) is a soft tissue tumor with a significant degree of morphologic and molecular heterogeneity. We employed integrative molecular profiling to discover and characterize molecular subtypes of LMS. Gene expression profiling was performed on 51 LMS samples. Unsupervised clustering demonstrated 3 reproducible LMS clusters. Array comparative genomic hybridization (aCGH) was performed on 20 LMS samples and demonstrated that the molecular subtypes defined by gene-expression showed distinct genomic changes. Tumors from the “muscle-enriched” cluster showed significantly increased copy number changes (p=0.04). Most muscle-enriched cases showed loss at 16q24 which contains FANCA, known to play an important role in DNA repair, and loss at 1p36 which contains PRDM16, whose loss promotes muscle differentiation. Immunohistochemistry was performed on LMS tissue microarrays (n=377) for five markers with high levels of mRNA in the muscle-enriched cluster (ACTG2, CASQ2, SLMAP,CFL2, MYLK) and demonstrated significantly correlated expression of the 5 proteins (all pairwise p < 0.005). Expression of the 5 markers was associated with improved disease-specific survival (DSS) in a multivariate Cox regression analysis (p < 0.04). In this analysis that combined gene expression profiling, aCGH and immunohistochemistry, we characterized distinct molecular LMS subtypes, provided insight into their pathogenesis, and identified prognostic biomarkers.
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DOI：
10.1158/1078-0432.ccr-08-1283
发表时间：
2009-02-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Beck AH;Espinosa I;Edris B;Li R;Montgomery K;Zhu S;Varma S;Marinelli RJ;van de Rijn M;West RB
通讯作者：
West RB
影响因子：
20.3
作者：
Lensch, MW;Tischkowitz, M;Bagby, GC
通讯作者：
Bagby, GC
影响因子：
11.2
作者：
Baird, K;Davis, S;Meltzer, PS
通讯作者：
Meltzer, PS
间充质肿瘤的分子图。
影响因子：
12.3
作者：
Henderson, Stephen R;Guiliano, David;Presneau, Nadege;McLean, Sean;Frow, Richard;Vujovic, Sonja;Anderson, John;Sebire, Neil;Whelan, Jeremy;Athanasou, Nick;Flanagan, Adrienne M;Boshoff, Chris
通讯作者：
Boshoff, Chris
影响因子：
4
作者：
Landis-Piwowar, Kristin R.;Milacic, Vesna;Dou, Q. Ping
通讯作者：
Dou, Q. Ping