基于双聚类挖掘癌症共享的基因功能模块  

Identification of gene functional modules shared by cancers based on biclustering

作　　者：张凡[1] 林爱华[1] 林美华[2] 丁元林[2] 饶绍奇[1,2] 

机构地区：[1]中山大学公共卫生学院,广州510080 [2]广东医学院公共卫生学院,东莞523808

出　　处：《遗传》2013年第3期333-342,共10页Hereditas（Beijing)

基　　金：广东省科技计划攻关项目(编号:2009A030301004);东莞市科技重点项目(编号:201108101015);广东医学院基金项目(编号:XG1001;XZ1105;STIF201122);国家自然科学基金项目(编号:30830104;31071166)资助

摘　　要：基因多效性是癌症遗传机制中的普遍现象,但罕见系统性的分析。文章提出采用双聚类挖掘基因功能模块的新思路探索癌症的共享分子机制和不同癌症间的关系。获取20种癌症的基因表达数据,应用改良t检验和倍数法筛选出至少在两种癌症中差异表达的基因,得到10417×20的数据矩阵;采用双聚类方法获得22个癌症共享的基因簇;进一步富集分析得到17个基因功能模块(Bonferroni校正后P<0.05),主要参与有丝分裂染色单体分离的调控、细胞分化、免疫和炎症反应、胶原纤维组织等生物过程;主要执行ATP结合和微管活动、MHCⅡ类受体活性、肽链内切酶抑制活性等分子功能;活动区域主要在细胞骨架、染色体、MHCⅡ蛋白质复合体、中间丝蛋白、胶原纤维等。基于模块构建癌症相关网络,显示胃癌、卵巢腺癌、宫颈鳞癌和间皮瘤等之间相关程度较高,而两种血液系统癌症(急性髓细胞性白血病与多发性骨髓瘤)分子机制与其他癌症存在较大差异。可见癌症共享的基因功能模块与多种生物机制有关,癌症之间相似性可能与组织起源、共同的致癌机制等有关。文章提出的基因多效性分析方法有助于解释人类复杂性疾病的共享分子机制。Pleiotropy is a common phenomenon in the genetics of cancers, which is rarely systematically evaluated. A novel idea for identifying shared gene functional modules using biclustering was proposed in this paper to explore the common molecular mechanisms among cancers and the relationships between different types of cancers. Gene expression datasets for 20 cancers were obtained. And genes differentially expressing in at least two types of cancers were selected using both moderated t-statistic and fold change to construct a 10417 × 20 matrix （gene-cancer matrix）. 22 gene clusters shared by cancers were found by using the biclustering method. Further, Gene Ontology （GO）-based enrichment analysisidentified 17 gene functional modules （Bonferroni corrected P 〈 0.05）. The involved biological processes primarily in- cluded regulation of chromatids separation during mitosis, cell differentiation, immune and inflammatory response, and collagen fibril organization. These modules undertook molecular functions of ATP binding and microtubule motor activity, MHC class II receptor activity, endopeptidase inhibitor activity and so on. And their activity sites were mostly located in cytoskeleton, chromosome, MHC protein complex, intermediate filament, fibrillar collagen and so on. The network con- structed based on these modules indicates that gastric cancer, ovarian adenocarcinoma, cervical cancer and mesothelioma were highly relevant to each other. However, the molecular mechanisms of two hematologic malignancies （acute myeloid leukemia and multiple myeloma） seem very different from other cancers. It can be seen that gene functional modules shared by cancers are associated with many biological mechanisms, and similarities among cancers are probably attributed to cel- lular origin and shared carcinogenic mechanisms. The proposed method for analysis of pleiotropy in this paper will help understand the common molecular mechanisms for complex human diseases.

关 键 词：癌症 基因多效性 双聚类 基因功能模块 

分 类 号：R730.5[医药卫生—肿瘤]