Department of Biology, University of Pisa, Italy.
Department of Endocrinology and Metabolism, Orthopedics and Traumatology, Occupational Medicine, University of Pisa, Italy.
Mutat Res. 2012 Apr-Jun;750(2):132-140. doi: 10.1016/j.mrrev.2011.12.003. Epub 2011 Dec 15.
Malignant pleural mesothelioma (MPM), a cancer of the serosal pleural cavities, is one of the most aggressive human tumors. In order to identify genes crucial for the onset and progression of MPM, we performed an extensive literature review focused on transcriptome studies (RTS). In this kind of studies a great number of transcripts are analyzed without formulating any a priori hypothesis, thus preventing any bias coming from previously established knowledge that could lead to an over-representation of specific genes. Each study was thoroughly analyzed paying particular attention to: (i) the employed microarray platform, (ii) the number and type of samples, (iii) the fold-change, and (iv) the statistical significance of deregulated genes. We also performed data mining (DM) on MPM using three different tools (Coremine, SNPs3D, and GeneProspector). Results from RTS and DM were compared in order to restrict the number of genes potentially deregulated in MPM. Our main requirement for a gene to be a "mesothelioma gene" (MG) is to be reproducibly deregulated among independent studies and confirmed by DM. A list of MGs was thus produced, including PTGS2, BIRC5, ASS1, JUNB, MCM2, AURKA, FGF2, MKI67, CAV1, SFRP1, CCNB1, CDK4, and MSLN that might represent potential novel biomarkers or therapeutic targets for MPM. Moreover, it was found a sub-group of MGs including ASS1, JUNB, PTGS2, EEF2, SULF1, TOP2A, AURKA, BIRC5, CAV1, IFITM1, PCNA, and PKM2 that could explain, at least in part, the mechanisms of resistance to cisplatin, one first-line chemotherapeutic drug used for the disease. Finally, the pathway analysis showed that co-regulation networks related to the cross-talk between MPM and its micro-environment, in particular involving the adhesion molecules, integrins, and cytokines, might have an important role in MPM. Future studies are warranted to better characterize the role played by these genes in MPM.
恶性胸膜间皮瘤（MPM）是一种发生在胸膜腔浆膜的癌症，是最具侵袭性的人类肿瘤之一。为了确定对 MPM 的发生和进展至关重要的基因，我们进行了广泛的文献综述，重点是转录组研究（RTS）。在这种研究中，大量的转录本被分析，而没有制定任何先验假设，从而防止了任何可能导致特定基因过度表达的先前建立的知识偏见。我们对每一项研究都进行了深入分析，特别注意：（i）所使用的微阵列平台，（ii）样本的数量和类型，（iii）失调基因的倍数变化，以及（iv）统计意义。我们还使用三种不同的工具（Coremine、SNPs3D 和 GeneProspector）对 MPM 进行了数据挖掘（DM）。为了限制可能在 MPM 中失调的基因数量，将 RTS 和 DM 的结果进行了比较。我们对一个基因成为“间皮瘤基因”（MG）的主要要求是在独立的研究中可重复地失调，并通过 DM 得到证实。因此，生成了一个 MG 列表，包括 PTGS2、BIRC5、ASS1、JUNB、MCM2、AURKA、FGF2、MKI67、CAV1、SFRP1、CCNB1、CDK4 和 MSLN，它们可能代表 MPM 的潜在新型生物标志物或治疗靶点。此外，还发现了一组包括 ASS1、JUNB、PTGS2、EEF2、SULF1、TOP2A、AURKA、BIRC5、CAV1、IFITM1、PCNA 和 PKM2 的 MG，它们至少可以部分解释对顺铂的耐药机制，顺铂是用于该疾病的一线化疗药物之一。最后，通路分析表明，与 MPM 与其微环境之间的串扰相关的共调控网络，特别是涉及粘附分子、整合素和细胞因子的网络，可能在 MPM 中发挥重要作用。未来的研究需要更好地描述这些基因在 MPM 中的作用。
