Concordance of copy number loss and down-regulation of tumor suppressor genes: a pan-cancer study.
Concordance of copy number loss and down-regulation of tumor suppressor genes: a pan-cancer study.
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DOI：
10.1186/s12864-016-2904-y
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发表时间：
2016-08-22
期刊：
影响因子：
4.4
通讯作者：
Zhao Z
中科院分区：
文献类型：
--
作者：
Zhao M;Zhao Z
肿瘤抑制基因（TSGs）编码的监护分子来控制细胞的生长。TSGs的基因组改变可能导致肿瘤发生并促进癌症进展。到目前为止，研究者主要研究TSGs中体细胞单核苷酸变异的功能效应。拷贝数变异（CNV）是遗传变异的另一种重要形式，经常参与癌症生物学和药物治疗，但文献中对TSG中CNV的研究较少。此外，在这个重要的基因集中，缺乏基因表达和CNV的组合分析。这样的研究可能会为基因剂量与肿瘤发生之间的关系提供更多的见解。为了满足这一需求，我们对TSGs中的CNV和基因表达进行了系统分析，以提供泛癌中TSGs中CNV和基因表达变化的系统视图。我们在5846个肿瘤样本中鉴定了1170个拷贝数增加或减少的TSG。其中，207个TSG倾向于具有拷贝数丢失（CNL），从中鉴定出15个CNL热点区域。功能富集分析显示，207个TSGs富集在癌症相关通路中，如P53信号通路和P53相互作用组。我们进一步使用来自匹配的肿瘤样本的数据进行CNV与基因表达的综合分析。我们发现81个TSGs在我们检查的肿瘤样本中具有一致的CNL事件和降低的基因表达。值得注意的是，7个TSG在至少50个肿瘤样品中显示一致的CNL和基因下调：MTAP（212个样品）、PTEN（139）、MCPH 1（85）、FBXO 25（67）、SMAD 4（64）、TRIM 35（57）和RB 1（54）。具体到MTAP，在14种癌症类型中发现了这种一致性，这一观察结果在文献中还没有太多报道。进一步基于网络的分析显示，这些具有一致CNL和基因下调的TSG高度相关。这项研究提供了泛癌症中CNV的草图。我们发现CNL和基因表达下调之间的系统一致性可能有助于更好地理解肿瘤发生和癌症进展中的TSG生物学。本文的在线版本（doi：10.1186/s12864-016-2904-y）包含补充材料，可供授权用户使用。
Tumor suppressor genes (TSGs) encode the guardian molecules to control cell growth. The genomic alteration of TSGs may cause tumorigenesis and promote cancer progression. So far, investigators have mainly studied the functional effects of somatic single nucleotide variants in TSGs. Copy number variation (CNV) is another important form of genetic variation, and is often involved in cancer biology and drug treatment, but studies of CNV in TSGs are less represented in literature. In addition, there is a lack of a combinatory analysis of gene expression and CNV in this important gene set. Such a study may provide more insights into the relationship between gene dosage and tumorigenesis. To meet this demand, we performed a systematic analysis of CNVs and gene expression in TSGs to provide a systematic view of CNV and gene expression change in TSGs in pan-cancer. We identified 1170 TSGs with copy number gain or loss in 5846 tumor samples. Among them, 207 TSGs tended to have copy number loss (CNL), from which fifteen CNL hotspot regions were identified. The functional enrichment analysis revealed that the 207 TSGs were enriched in cancer-related pathways such as P53 signaling pathway and the P53 interactome. We further performed integrative analyses of CNV with gene expression using the data from the matched tumor samples. We found 81 TSGs with concordant CNL events and decreased gene expression in the tumor samples we examined. Remarkably, seven TSGs displayed concordant CNL and gene down-regulation in at least 50 tumor samples: MTAP (212 samples), PTEN (139), MCPH1 (85), FBXO25 (67), SMAD4 (64), TRIM35 (57), and RB1 (54). Specifically to MTAP, this concordance was found in 14 cancer types, an observation that is not much reported in literature yet. Further network-based analysis revealed that these TSGs with concordant CNL and gene down-regulation were highly connected. This study provides a draft landscape of CNV in pan-cancer. Our findings of systematic concordance between CNL and down-regulation of gene expression may help better understand the TSG biology in tumorigenesis and cancer progression. The online version of this article (doi:10.1186/s12864-016-2904-y) contains supplementary material, which is available to authorized users.
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