鼻咽癌的表观遗传学研究进展

表观遗传学是功能基因组学的重要组成部分,它实际上是研究理化、生物等环境因素以及饮食习惯等对遗传因素的作用,并由这一作用引起DNA序列以外的遗传物质改变.鼻咽癌是我国南方常见恶性肿瘤,具有明显的家族聚集倾向,存在基因组不稳定性,易受理化、生物等环境因素的影响,是多基因遗传性肿瘤.鼻咽癌这种独特病因体系提示:鼻咽癌是研究肿瘤表观遗传修饰的最佳模型之一.主要从DNA甲基化、组蛋白修饰、染色质重构和非编码RNA的调控4方面对鼻咽癌表观遗传学研究进展进行综述并针对性地提出了一些新的建议,目的是为进一步探究鼻咽癌表观遗传学发病机制,更好地全面理解鼻咽癌的病因发病机制网络体系,寻找鼻咽癌高危易感人群的筛查、早期诊断、治疗、预后判断的表观遗传修饰分子标志物开辟新的前景.     

白癜风相关基因研究进展

白癜风是一种多基因遗传性疾病,虽然环境是白癜风的发病因素,遗传因素在白癜风发病机制中也起着重要作用.近年来不断有与白癜风相关基因的报道,综述近几年关于白癜风易感基因定位及相关基因的研究,为进一步研究白癜风的病因提供思路.     

白癜风相关基因研究进展

白癜风是一种多基因遗传性疾病,虽然环境是白癜风的发病因素,遗传因素在白癜风发病机制中也起着重要作用。近年来不断有与白癜风相关基因的报道,综述近几年关于白癜风易感基因定位及相关基因的研究,为进一步研究白癜风的病因提供思路。     

天然免疫分子乳铁蛋白抑制鼻咽癌的发生发展

鼻咽癌是一种多基因遗传性肿瘤,其发病与遗传因素和环境因素密切相关,基因与环境因素间存在复杂的交互作用. 本课题组通过全基因组杂合性丢失扫描及比较基因组杂交,发现鼻咽癌中3号染色体短臂存在高频缺失,通过鼻咽癌家系连锁分析,发现染色体3p21区域为鼻咽癌易感基因区,随后通过表型克隆策略在该染色体区域分离鉴定了鼻咽癌候选易感/抑瘤基因LTF. LTF基因编码的乳铁蛋白是一种广泛分布于哺乳动物乳汁、鼻咽分泌物、泪液等分泌液中的天然免疫分子,在正常鼻咽部高表达而在鼻咽癌组织中表达显著下调,且与鼻咽癌的临床进展及侵袭转移密切相关. 病例-对照关联分析发现LTF基因中2个单核苷酸多态位点与鼻咽癌发病风险密切相关,且多态性改变可影响LTF基因的表达水平. 我们发现乳铁蛋白能与EB病毒在人B细胞表面的受体CD21结合,阻断EB病毒入侵宿主B细胞,并抑制EB病毒由B细胞向鼻咽上皮细胞的传递,在鼻咽上皮的癌变过程中起保护作用. 我们还发现LTF能通过MAPK和AKT等通路抑制鼻咽癌细胞的增殖和侵袭转移. 这些结果表明乳汁中的天然成份乳铁蛋白在鼻咽癌等EB病毒相关疾病的防治中具有重要的应用前景.     

冠心病易感基因的筛选

作为一种多基因疾病 ,冠心病是由遗传和环境因素共同作用的结果 ,在许多国家是主要的死因之一。由于目前冠心病的发病机制尚不十分清楚 ,阻碍了其易感基因的定位分离研究。冠心病遗传因素的确定 ,显然将有助于其易感基因定位分离研究。迄今除发现了个别的相关基因外 ,绝大部分的遗传易感性相关基因尚未被发现 ,其研究仍然存在许多问题。为此 ,本文就其易感基因可能的研究策略和方法作一综述。这些方法同样也适用于诸如中风、外周血管阻塞、高血压、心力衰竭等心血管疾病以及其它多基因疾病     

《自然-遗传学》：研究发现散发性鼻咽癌易感基因

《自然-遗传学》（Nature Genetics）5月30日发表了由中国科学院院士、中山大学肿瘤防治中心曾益新带领的团队。与来自国内和新加坡等国科学家合作完成的一项研究。研究人员在世界上首次进行了基于大规模人群和全基因组水平的散发性鼻咽癌易感基因筛查研究。发现了3个新的易感基因位点,同时进一步确认了人类白细胞抗原（HLA）基因与鼻咽癌发病风险的相关性。     

复杂疾病基因定位策略与肿瘤易感基因鉴定

对于不存在某单一基因位点经典的孟德尔显性或隐性遗传模式的疾病,称为复杂疾病,肿瘤是最常见的类型之一 . 目前,以连锁和相关分析为基础的功能克隆、功能候选克隆、定位克隆、定位候选克隆、系统生物学等复杂疾病易感基因定位策略逐渐发展起来 . 其中,系统生物学策略由于整合了从 DNA 到蛋白质的各个层面的信息,对复杂疾病基因调控网络做出了良好诠释,使其成为最有潜力的方法之一 . 目前,虽然已有近 100 种肿瘤 / 遗传性癌综合症的易感基因被鉴定出来,但未来的复杂疾病易感基因定位工作仍充满了挑战 .     

孤独症的遗传学和神经生物学研究进展

孤独症是一种遗传度高达90%的多基因复杂疾病,具有典型的遗传和表型异质性,并受到环境因素的影响.本文对近年来孤独症遗传学、表观遗传学和神经生物学3方面的进展进行了简要综述.细胞遗传学法、全基因组扫描及候选基因法是孤独症分子遗传学研究中较为常见的3种方法.虽然应用上述方法发现了一些孤独症易感基因集中的染色体区域,但确切的致病或易感基因仍未被检出.因而,越来越多的关注被集中于如何提高样本同质性、如何将遗传学机制与环境作用相联系、如何提高微效基因的检出率上.在提高样本同质性方面,功能核磁共振及交叉表型的研究正在进行.同时,表观遗传学的研究可以联系遗传与环境因素,从而更好地解释孤独症的发病机制.目前,对染色体上表观遗传与遗传共同调控的区域,如7号和15号染色体长臂,进行了大量研究.在神经生物学方面,神经递质、神经发育及神经免疫学假说均有一定的进展.其中,针对神经递质的研究主要集中于5-羟色胺、?-氨基丁酸及谷氨酸.在神经发育假说方面,神经发育相关蛋白,如肝细胞生长因子、神经生长因子及Reelin,研究得较为深入.     

精神分裂症易感基因

精神分裂症是一类遗传倾向性较高的多基因疾病。近年来,随着遗传学和分子生物学为主的多学科研究技术的快速发展,不断有新的易感基因报道;一些重要易感基因的生物学功能及其在该疾病发病机制中的作用研究也取得了一定进展。     

探讨HLA-DR_4基因与类风湿关节炎的相关性

RA是一种慢性自身免疫性疾病,其发病机制目前还不是很清楚,有大量的研究表明RA为多基因遗传性疾病,其中HLA-DR_4基因不仅和RA的发病率相关,并且和病情的严重程度有关。检测HLA-DR_4基因,对于预测RA易感患者同时估计和判断RA患者的病情进程和预后都有特殊的意义。     

Lack of association between human leukocyte antigen-E alleles and nasopharyngeal carcinoma in Tunisians

Nasopharyngeal carcinoma (NPC), a cancer with a remarkable geographical and worldwide ethnic distribution, has been strongly associated with human leukocyte antigen (HLA) class I genes. The presence of additional HLA risk factors has been suggested by several reports. In the present study, we analyzed the implication of HLA-E gene polymorphisms in NPC susceptibility in Tunisians, a population characterized by an intermediate incidence of NPC with specific clinical features. Peripheral blood DNA was obtained from 185 patients with NPC and 177 matched controls. Genotyping for three single-nucleotide polymorphisms, codon 83Gly/Arg, codon 157Arg/Gly, and codon 107Arg/Gly, was performed using the polymerase chain reaction method. The HLA-E*01:01 and HLA-E*01:03 were the only alleles found among Tunisians. The HLA-E*01:03 allele had a slight increase in patients with NPC (43%) compared with controls (37%), but the difference did not reach a statistical significance. Our results show the lack of association between HLA-E alleles and NPC in the Tunisian population. This is not in agreement with the previous studies, suggesting a potential implication of HLA-E gene polymorphisms in the susceptibility to NPC among populations with high-risk incidence. Our study further supports the dissimilarity of NPC between populations with different NPC incidence.     

The DLC-1 -29A/T polymorphism is not associated with nasopharyngeal carcinoma risk in Chinese population

Deleted in liver cancer-1 (DLC-1), encoding a Rho GTPase-activating protein (GAP), is considered as a promising candidate tumor suppressor gene in nasopharyngeal carcinoma (NPC). The single-nucleotide polymorphism (SNP) -29A/T upstream of ATG start codon was found when gene mutation profile of DLC-1 in NPC was analyzed. To evaluate the correlation between SNP -29A/T in the promoter region of DLC-1 gene and risk of NPC, a total of 521 samples from a Chinese population, including 320 healthy individuals and 201 NPC patients, were collected for SNP analysis by PCR-single-strand conformation polymorphism and sequencing. The differences in allele and genotype frequencies between NPC patients and controls were tested using logistic regression statistical method. No significant differences were found in allele or genotype frequencies between NPC patients and controls or among different NPC clinical stages. Hence, our data indicate that the SNP -29A/T of DLC-1 gene is not associated with NPC susceptibility.     

Diet and nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is a disease with a remarkable racial and geographical distribution. It is very rare (incidence of less than 1 per 100,000 person-years) in most parts of the world and only a handful of populations are known to deviate from this low-risk profile, which include people of southern China. Eskimos and other natives of the Arctic region, natives of southeast Asia, and mainly Arab populations of north Africa and Kuwait. There is now convincing evidence implicating dietary factors as the primary cause of NPC among Chinese. A series of case-control studies conducted in various Chinese populations with distinct risks of NPC, ranging from the very high-risk Cantonese to the relatively low-risk Northern Chinese, have suggested that ingestion of salted fish and other kinds of preserved foods by the Chinese constitutes the most important cause of NPC development among these people. Preliminary data on Malays in southeast Asia, Eskimos in Alaska, and Arabs of north Africa also suggest that ingestion of preserved foods by these population groups may be responsible for their raised incidence of NPC.     

MicroRNAs: Potential diagnostic markers and therapeutic targets for EBV-associated nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is a highly malignant cancer with local invasion and early distant metastasis. NPC is highly prevalent in the Southern China and South-eastern Asia. The genetic susceptibility, endemic environment factors, and Epstein-Barr virus (EBV) infection are believed to be the major etiologic factors of NPC. Once metastasis occurs, the prognosis is very poor. It is urgently needed to develop biomarkers for early clinical diagnosis/prognosis, and novel effective therapies for nasopharyngeal carcinoma. In this paper, we systematically reviewed the current progress of miRNA studies in NPC. It has been shown that both host encoded miRNAs and EBV encoded miRNAs play key roles in almost all the steps of epithelia cell carcinogenesis, including epithelial-mesenchymal to stem-like transition, cell growth, migration, invasion, and tumorigenesis. More importantly, some miRNAs could be secreted out and play a role in the microenvironments. The level of sera miRNAs is correlated with the copy numbers of host miRNAs in tumor biopsies. Promising results of gene therapy have been also achieved by lentiviral delivered miRNAs. Taken together, cell free miRNAs would be potential biomarkers of early clinical diagnosis/prognosis; while some miRNAs could be further developed into therapeutic agents in the future.     

Diet and nasopharyngeal carcinoma

Abstract Nasopharyngeal carcinoma (NPC) is a disease with a remarkable racial and geographical distribution. It is very rare (incidence of less than 1 per 100 000 person-years) in most parts of the world and only a handful of populations are known to deviate from this low-risk profile, which include people of southern China, Eskimos and other natives of the Arctic region, natives of southeast Asia, and mainly Arab populations of north Africa and Kuwait. There is now convincing evidence implicating dietary factors as the primary cause of NPC among Chinese. A series of case-control studies conducted in various Chinese populations with distinct risks of NPC, ranging from the very high-risk Cantonese to the relatively low-risk Northern Chinese, have suggested that ingestion of salted fish and other kinds of preserved foods by the Chinese constitutes the most important cause of NPC development among these people. Preliminary data on Malays in southeast Asia, Eskimos in Alaska, and Arabs of north Africa also suggest that ingestion of preserved foods by these population groups may be responsible for their raised incidence of NPC.     

环状RNA参与鼻咽癌发生发展

环状RNA(circular RNA,circRNA)是一种具有共价闭环结构的非编码RNA(non-coding RNA,ncRNA),因其具有高稳定性、进化保守性和组织表达特异性的特点,越来越受到人们的关注。现有研究表明,circRNA参与恶性肿瘤等多种疾病的发生发展过程。鼻咽癌是一种起源于鼻咽上皮的恶性肿瘤,在中国华南和东南亚地区高发,发病与EB病毒（Epstein-Barr virus,EBV）感染密切相关。目前放疗和化疗是鼻咽癌治疗的主要手段,复发和远处转移是鼻咽癌患者死亡的主要原因。近年研究表明,circRNA作为基因表达调节因子,在鼻咽癌发生发展过程中发挥着重要的作用,影响着鼻咽癌的进展。本文主要综述了鼻咽癌中表达异常的circRNA,包括EB病毒编码的circRNA,在鼻咽癌发生发展中的研究现状,探讨了circRNA作为鼻咽癌患者治疗的潜在靶点以及诊断和预后标志物的可能性。     

一个新硝基还原酶基因NOR1编码区单核苷酸多态及与鼻咽癌的关联分析

NOR1基因是中南大学湘雅医学院肿瘤研究所克隆的一个鼻咽癌表达下调新基因,生物信息学预测NOR1基因含有硝基还原酶结构域,该基因可能参与亚硝胺类化学致癌物在体内的代谢过程,从而与鼻咽癌的发生密切相关.通过采用病例-对照的研究方法,利用测序技术对144名鼻咽癌患者和匹配的144名正常人NOR1基因编码区单核苷酸多态(coding region single nucleotide polymorphisms, cSNPs)进行基因分型,关联分析结果显示所检测到的两个cSNPs之间存在连锁不平衡,且均与鼻咽癌发病相关,两个cSNPs及它们所组成的单倍型相对危险度分别为1.36、1.64和1.37.两个cSNPs的多态性改变均使NOR1基因编码蛋白一级结构发生了变化,这种改变可能影响NOR1基因编码蛋白的结构和功能.研究进一步支持了NOR1基因与鼻咽癌的发生发展可能存在密切的关系.