范可尼贫血肿瘤相关通路的基因集富集分析

Enrichment analysis of fanconi anemia gene expression profiles in cancer related genesets

目的探讨范可尼贫血（FA）患者高肿瘤易感性的潜在机制与原因。方法采用基因集富集分析（Genesetenrichmentanalysis，GSEA）对NCBIGEO数据库中21例FA患者和11例健康志愿者的骨髓单个核细胞基因表达谱进行比较研究，分析其在肿瘤相关通路及肿瘤相关基因集中的富集特征与核心富集基因。然后利用对基因本体学（Geneontology）生物过程和结构基因组相关基因集的富集分析，进一步阐释了该病高肿瘤易感性的潜在原因。结果FA患者在抗Bcl-2抑制剂相关基因集和成纤维细胞生长因子、胰岛素及胰岛素样生长因子（IGF）信号通路介导的肿瘤基因集中有显著富集特征。其中核心富集基因D4S234E、SST、FGF、IGF、FGFR和IGFBP等的高表达与促进肿瘤形成及耐药相关。在生物学过程上，FA患者细胞外分子的生物合成和结构与对照组具有显著差异。在结构基因组相关分析中发现，包含上述IGF2在内的转录起始位点附近具有模体RRCAGGTGNCV及CCT-NTMAGA的基因集具有富集特征，其中前者与肿瘤发生的关键转录因子TCF3匹配。结论FA患者的高肿瘤易感性与其体内在关键转录因子介导下的肿瘤相关细胞因子、激素等内环境变化密切相关。

Objective To investigate the underlying tumor susceptibility mechanisms and reasons for the high risk of cancer in Fanconi anemia （FA）. Methods Gene Set Enrichment Analysis （GSEA） was performed to compare gene expression profiles between 21 FA patients＇ bone marrow（BM） mononuclear cell （MNC） and 11 normal controls in cancer related gene sets from NCBI GEO database, then core enriched genes were identified by further investigation. Through enrichment analyzing biological processes of gene on- tology sets and structural genomic gene sets between FA expression profiles and control, more details related with its tumor susceptibility had been revealed. Results Compared with normal control, gene expression in FA group had significant been enriched in resistance to Bcl-2 inhibitor gene set, fibroblast growth factors sig- nalling pathways, insulin and insulin-like growth factors （IGF） signalling pathways induced cancer genesis gene sets. The high level of D4S234E, SST, FGFs, IGFs, FGFRs and IGFBP expression provided an initiate environment for tumorgenesis and drug resistance. There were significant differences in biogenesis extracellu- lar molecules and cytomembrane structure organizations between FA and control. Genes with promoter regions around transcription start sites containing either motif RRCAGGTGNCV or CCTNTMAGA were enriched and those former genes match annotation for tumorgenic transcription factor 3 （TCF3）. Conclusions The high tumor susceptibility of FA patients may be closely related with the dramatic changes in cancer related growth factors and hormones environment. This study provides new insights into tumor susceptibility mechanism in FA patients.