According to the report from the Center for Disease Control and Prevention (CDC), 596 339 peoples died of cancer in the United States in 2011^{[ 1]}. Worldwide, there were 8.2 million deaths from cancer in the world in 2012^{[ 2]}. It is now well understood that many factors can cause the genetic material (DNA) of a cell damage or change, producing mutations that affect normal cell growth and division. When this happens, cells do not die when they should and new cells form when the body does not need them. The extra cells may form a mass of tissue called a tumor. Therefore, gene alteration plays a key role in the development of tumor. Since the completion of the Human Genome Project (HGP) in April, 2003, enormous progress has been made in the understanding of mechanism of tumorigenesis as well as in prevention, diagnosis and treatment of tumor because of the breakthrough in tumor molecular research such as genetic and epigenetic alterations (gene copy number alteration, single nucleotide variation, promoter methylation), microRNA (miRNA), gene expression, alternative splicing, chromosomal rearrangements, signaling pathway, exome, genome-wide association studies and advancement of sequencing technologies, informatics, and microarray technologies. The Cancer Genome Atlas (TCGA) pilot project initiated in 2006 confirmed that an atlas of changes could be created for specific cancer types. Understanding how such changes interact to drive the disease will lay the foundation for improving cancer prevention, early detection and treatment^{[ 3]}. To give clinical laboratorians and clinicians an update on the new development in the tumor-associated gene studies, we publish this special issue of "Tumor-associated Genes".

This special issue of "Tumor-associated Genes" includes 3 review articles and 2 original research papers. The first review paper entitled "The Human Cancer Genome: Laboratory Analysis and Clinical Application" is offered by Dr. LI Siyong at the Emory University School of Medicine in Atlanta, USA. This review article first provides an overview on the human genome including normal human genome structure, transcriptome, exome, and common genetic variation [single nucleotide polymorphism/variants (SNP/Vs) as well as copy number variants (CNVs)]. Then, the author introduces the technological advance in the analysis of human genome with emphasis on next generation sequencing (NGS) platforms such as Roche 454 GS FLX Titanium and Junior systems (Roche Applied Sciences, Penzberg, Germany), the Life Technology ABI/5500 SOLiDTM system (Life Technologies, Carlsbad, CA), Illumina HiSeq2000/2500 and MiSeq systems (Illumina, San Diego, CA), Helicos from BioSciences HeliScope, SMRT from Pacific Biosciences and Oxford Nanopore Technologies and the applications of these NGS systems. The author further summarizes the new discoveries by human cancer genomic studies in signal transduction pathways, epigenomic regulation, genomic stability, RNA splicing machinery, metabolism and other new features of the human cancer genome. Finally, the author elucidates current clinical applications of human cancer genomics in cancer diagnosis, classification and prognostication, monitoring of treatment, response and relapse of cancer. After reading this very comprehensive review, our reader will gain a better understanding of cancer genome, tumor-related genomic tests and their clinical applications.

MiRNA is another important topic of this special issue of "Tumor-associated Genes". Since the discovery of miRNA in 1993^{[ 4]}, numerous studies have been conducted and researchers have found that these small RNA molecules typically reduce the translation and stability of mRNAs, including those genes that mediate processes in tumorigenesis, such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis and invasion. Given the critical role that miRNAs play in tumorigenesis process and their disease specific expression, they hold potential as therapeutic targets and novel biomarker of tumor^{[ 5]}. In this special issue, we select 3 articles related to miRNA: 1 review and 2 original research papers. The title of the review article is "Relationship between microRNA-related single nucleotide polymorphism and tumors". In this review article, the authors first briefly introduce miRNA and their biological functions, and then summarize miRNA-related single-nucleotide polymorphisms (SNPs) and their association with tumorigenesis using miRNA gene SNPs and miRNA target gene SNPs as examples. This review article provides our readers with a timely update on miRNA related SNPs and their potential roles in the diagnosis and personalized therapy of tumor. In addition, the 2 original research papers serve as examples that demonstrate the role of miRNA in the regulation of proliferation and migration of tumor cells. In the paper, "Inhibition of down-regulated miRNA-221 and miRNA-222 in human breast cancer MCF-7 cell line to tumor cell proliferation and migration", the authors constructed antisense miR-221/222 and transfected them into a human breast cancer cell line MCF-7 to knock down miRNA-221/222 expression and found that decrease in miRNA-221/222 expression up regulated tissue inhibitor of metalloproteinase 3 (TIMP3) expression at mRNA level and down regulated (a disintegrin and metalloprotease (ADAM17) at protein level. The authors further found that knockdown of miRNA-221/222 inhibited the proliferation and migration of MCF-7 cells. It was concluded that the inhibition of MCF-7 cells proliferation and migration by antisense miRNA-221/222 was through up-regulation of TIMP3. In the other paper, "Modulation of the proliferation,migration and SIRT1 expression of prostate cancer cell PC-3 by miRNA-221 and miRNA-222", a prostate cancer cell line PC-3 was transfected with antisense miRNA-221/222 and the authors showed that the knockdown of miRNA-221/222 also inhibited the proliferation and migration of PC-3 cells, while up regulated the expression of SIRT1, a member of the sirtuin family of proteins, at protein level, but the mechanism underlying the inhibition of SIRT1 was unclear. The readers can see that the same antisense miRNA transfected into 2 different cancer cell lines can generate the same cellular responses, but the regulatory pathways may be different.

Finally, this special issue also collects a review article entitled "Research progress on the correlation of single nucleotide polymorphism with the LTA susceptibility of gastric cancer" to demonstrate the importance of gene polymorphisms in the development of cancer. The authors use several SNPs of lymphotoxin-alpha( LTA) gene including LTA rs909253(A/G), rs1041981(C/A), rs2229094(T/C),rs746868(G/C)as examples to show the potential role of these SNPs in the susceptibility to gastric carcinogenesis. As the authors point out, the results of these studies are inconsistent due to difference in population, race, geography and environment, and therefore non-genetic factors should be kept in mind when performing SNP studies.

In summary, this special issue of "Tumor- associated Genes" will give our readers up-to-date information on human cancer genome, genetic polymorphisms, and miRNAs in the field of cancer research. We hope that the information presented here will promote more studies on tumor-associated genes and more clinical applications of tumor-associated gene tests in the field of laboratory medicine in the genomic era.

编者按:近年来,随着肿瘤相关基础研究进展和一些技术方法的成熟和应用,如分子遗传、信号转导、生物信息学、蛋白质组学、基因组学、DNA重组、杂交瘤技术和生物芯片技术等,越来越多的肿瘤相关基因被发现,包括癌基因、抑癌基因和DNA修复基因。多数肿瘤的发生与基因改变有关,包括点突变、扩增、重排、缺失或甲基化状态等改变。为了让读者对肿瘤基因有一个新的了解,本刊特组织了一期“肿瘤相关基因”专题,并邀请美国南卡罗来纳医科大学朱玉胜教授撰写了题为“From the Human Genome Project to the Cancer Genome Atlas, Are You Ready?”的述评,还邀请美国埃默里大学医学院病理检验科李仕勇教授撰写了题为“The Human Cancer Genome: Laboratory Analysis and Clinical Application”的综述。本刊特将这两篇文章全文译成中文,以飨读者。

根据美国疾病预防控制中心(Center for Disease Control and Prevention,CDC)的报道,美国2011年因癌症而死亡的病例高达596 339例^{[ 1]}。在2012年,世界上大约有820万人因癌症而死亡^{[ 2]}。现在已知,许多因素可导致细胞基因(DNA)损伤或改变,因而产生的突变可影响正常细胞的生长与分裂。在此情况下,细胞获得永生性,同时机体产生不需要的新细胞。这些额外的细胞形成一种组织,即所谓的肿瘤。因此,在肿瘤的发展过程中,基因改变起到非常关键的作用。自从2003年4月人类基因组(Human Genome Project,HGP)计划完成以来,人类在肿瘤发生机制、预防、诊断、治疗上的认知有了巨大的进步。这些进步归功于肿瘤分子生物学研究在以下领域所取得的突破,如:基因与表观遗传改变(基因拷贝数改变、单核苷酸变异、启动子甲基化)、微小RNA(microRNA,miRNA)、基因表达、选择性剪接、染色体重组、信号通路、外显子组,全基因组关联研究以及测序技术、信息学与微阵列技术上的进步。始于2006年的癌症基因图谱(The Cancer Genome Atlas,TCGA)先导计划证实了我们可以确定特异癌症类型的基因改变图谱。了解此类因基因改变的相互作用是如何导致癌症将为改进癌症的预防、早期检测与治疗奠定基础^{[ 3]}。为了让临床实验室专业人员和临床医生对肿瘤相关基因研究有一个最新的了解,我们组织了本期“肿瘤相关基因”专题。

本专题包括了3篇综述与2篇研究性文章。第一篇综述“The Human Cancer Genome: Laboratory Analysis and Clinical Application”由美国亚特兰大埃默里大学医学院的李仕勇教授撰写。首先,这篇综述对人类基因组进行了总体概述,包括正常人类基因组结构、转录组、外显子组以及常见基因变异[单核苷酸多态性/变异(SNP/V)以及拷贝数变异(CNV)]等内容。接着,作者对人类基因组相关分析技术的进展进行了介绍,着重介绍了下一代测序(next generation sequencing ,NGS)平台,如:Roche 454 GS FLX Titanium与Junior系统(Roche Applied Sciences, 潘茨堡, 德国)、Life Technology ABI/5500 SOLiDTM系统(Life Technologies, 卡尔斯巴德, 美国加利福尼亚州)、Illumina HiSeq2000/2500 与MiSeq系统(Illumina, 圣地亚哥, 美国加利福尼亚州)、BioSciences HeliScope的Helicos, Pacific Biosciences and Oxford Nanopore Technologies的SMRT以及这些NGS系统的应用。作者进而总结了人类癌症基因组研究在以下几方面的新发现:信号转导通路、表观基因组调节、基因组稳定性、RNA剪接机制、代谢与人类癌症基因组的其它新特点等。最后,作者对人类癌症基因组学在癌症诊断、分类、预后、治疗监测、治疗反应与复发等方面的临床应用进行了阐述。在阅读完这篇非常全面的综述之后,相信读者将会对癌症基因组、肿瘤相关基因学检测以及他们的临床应用有一个更进一步的认知。

miRNA是本专题“肿瘤相关基因”另一个重要的主题。自从1993年发现miRNA以来^{[ 4]},研究人员对其进行了广泛的研究,发现这些小RNA分子可以降低许多基因mRNA的翻译及其稳定性,包括调解肿瘤生成过程的基因,如:炎症、细胞周期调节、应激反应、分化、凋亡以及侵袭。基于miRNA在肿瘤发生过程的重要作用及其在特定肿瘤中的特异表达,其可能成为治疗靶向与新型的肿瘤标志物^{[ 5]}。在这一专题中,我们挑选了3篇有关miRNA的文章,包括1篇综述与2篇研究性文章。在题为“microRNA相关单核苷酸多态性与肿瘤的关系”的综述中,作者首先简要介绍了miRNA以及它的生物学功能,并以miRNA基因单核苷酸多态性(SNP)与miRNA靶向基因SNP为例,总结了有关miRNA SNP以及其与肿瘤生成的相关性。这篇综述在miRNA相关SNP以及它们在肿瘤的诊断与个体化治疗中的潜在作用等方面提供了一个及时的、最新的介绍。另外2篇研究性文章作为实例以展示miRNA在肿瘤细胞增殖与迁移调节中的作用。在“下调人乳腺癌MCF-7细胞系miRNA-221和miRNA-222表达对抑制肿瘤细胞增殖及迁移能力的探讨”一文中,作者构建了反义miRNA-221和miRNA-222并将其转染至人类乳腺癌细胞系 MCF-7细胞中,从而敲低miRNA-221和miRNA-222表达。作者发现miRNA-221、miRNA-222表达的降低可上调组织金属蛋白酶抑制剂3(tissue metalloproteinase inhibitor 3,TIMP3) mRNA的表达,但下调金属蛋白酶17(adisintegrin and metalloprotease 17,ADAM17)蛋白表达。作者进而发现,通过敲低miRNA-221和miRNA-222,可以抑制人乳腺癌细胞系MCF-7的增殖与迁移能力。据此得出结论,反义miRNA-221和miRNA-222是通过上调TIMP3的表达对MCF-7细胞的增殖与迁移能力实施抑制作用。在“miRNA-221和miRNA-222对前列腺癌细胞PC-3的增殖、迁移及SIRT1表达的调控”一文中,作者通过将miRNA-221和miRNA-222反义抑制质粒转染至前列腺癌细胞PC-3中,证明敲低miRNA-221和miRNA-222表达也可以抑制PC-3细胞的增殖与迁移,而上调沉默信息调节因子1(silent information regulator 1,SIRT1;隶属于sirtuin家族)蛋白的表达,但其机理目前还不清楚。读者可以了解到,相同的反义miRNA转染两个不同的癌症细胞系,可以生成相同的细胞应答,但是其调节通路可能是不一致的。

最后,这个专题还包括“ LTA单核苷酸多态性与胃癌易感性关系的研究进展”一文,以表明在癌症的发展过程中基因多态性的重要性。作者运用了几个淋巴毒素-α( LTA)基因SNP为例,包括LTA rs909253(A/G)、rs1041981(C/A)、rs2229094(T/C)与rs746868(G/C),展现了这些SNP在胃癌易感性方面的潜在作用。正如作者所指出的,此类研究尚未得出一致性的结论,这可能与研究人群、种族、地域及环境等不同因素的影响有关。因此,在进行SNP研究时,应当考虑这些非基因影响因素。

总的来说,这个“肿瘤相关基因”专题给我们的读者提供了许多癌症研究领域中与人类癌症基因组、基因多态性以及miRNA有关的最新信息。我们希望这些信息能够推进更多的有关肿瘤相关基因的研究,并且能够促进肿瘤相关基因检测在这个处于基因组时代的检验医学领域得到更多的临床应用。