Association of ERCC1 polymorphisms and susceptibility to nasopharyngeal carcinoma

The normal function of excision repair cross complementing group 1 (ERCC1) is essential for maintaining genomic integrity and preventing cellular neoplastic transformation, and multiple studies have reported an association between ERCC1 polymorphisms and increased risk of cancers. To test whether the genetic variants of ERCC1 gene modify the risk of nasopharyngeal carcinoma (NPC), we compared the 8092 C > A and 19007 C > T single nucleotide polymorphisms (SNPs) and the haplotypes of ERCC1 between 267 patients with NPC and 304 healthy controls. Linkage disequilibrium was observed between the two SNPs loci (D' = 0.861). Significant differences of allele frequencies were found for ERCC1 8092C > A between the cases and controls. Individuals with 8092 C allele showed 1.411-fold (OR = 1.411, 95% CI, 1.076-1.850, P = 0.014) increased risk of developing NPC, and the CC haplotype was associated with a significantly increased risk of NPC (OR = 1.712; 95% CI, 1.211-2.421; P = 0.013). No interactions were found between 8092C > A polymorphism and genders, smoking status and alcohol consumption. These results suggested that the polymorphism of ERCC1 8092 C > A might be a contributing factor in the development of NPC in Chinese population.     

ATM基因单核苷酸多态性与鼻咽癌易感性及复发的相关性

目的:探讨ATM基因单核苷酸多态性与鼻咽癌易感性与复发的关系.方法:采用病例对照研究,采集来自北方地区不同医院的鼻咽癌病人193例、正常人群231例静脉血,酚-氯仿法提取基因,Taqman real-time PCR方法及SDS软件对ATM基因型进行分型.SPSS 13.0软件包进行数据分析,以χ2检验比较SNPs基因型在病例与对照之间分布的差异,以单因素和多因素logistic回归计算比值比(odds ratio,OR)及95%可信区间(confidence interval,CI).结果:单因素分析显示,ATM126713位点的各基因型与鼻咽癌易感性不相关,P值0.075,OR值1.422,95%CI为0.963~2.199.但ATM126713位点的杂合基因型(G/A)经校正年龄、性别、吸烟状态后显示与鼻咽癌易感性相关,P值0.024,OR=1.636,95%CI为1.067~2.509.ATM126713位点各基因型与鼻咽癌复发不相关.结论:ATM126713位点G/A杂合型基因是鼻咽癌风险基因型,ATM126713位点各基因型与鼻咽癌复发无相关性.     

OPN基因多态性与广西壮族人群鼻咽癌易感性的关系

目的研究骨桥蛋白(osteopontin,OPN)基因单核苷酸多态性及其单倍型与广西壮族人群鼻咽癌(nasopharyngeal carcinoma,NPC)易感性的关系。方法采用病例-对照研究方法,收集2010-03-01-2013-03-20入住右江民族医学院附属医院的广西壮族鼻咽癌患者150例,同时随机选取2012-01-01-2012-08-01右江民族医学院附属医院常规体检的广西壮族人150名作为对照。采用单碱基延伸PCR技术和DNA测序法,检测150例广西壮族鼻咽癌患者和150名壮族对照者的OPN基因rs11728697和rs4754位点单核苷酸多态性,并分析OPN基因的单倍型频率。结果在OPN基因rs11728697位点上,携带CT基因型的个体相比携带常见的CC基因型个体罹患鼻咽癌的风险更高,OR=1.78,95%CI为1.05~2.98,χ2=5.863,P=0.033;但TT基因型并不增个体罹患鼻咽癌的风险,OR=0.92,95%CI为0.55~1.77,χ2=0.012,P=0.921。同时,鼻咽癌组在该位点的等位基因型频率与对照组的频率相比差异无统计学意义,OR=1.14,95%CI为0.69~1.45,χ2=0.545,P=0.466。在OPN基因rs4754位点上,对照组和鼻咽癌组的基因型及等位基因型频率分布差异无统计学意义,P>0.05。对照组和鼻咽癌组的单倍型频率分布差异亦无统计学意义,P>0.05。结论在广西壮族人群中,OPN基因rs11728697位点的CT基因型可能增加个体鼻咽癌的易感性,而rs4754位点的多态性与鼻咽癌的易感性无关。     

Interleukin-1B (IL-1B) polymorphisms and gastric mucosal levels of IL-1beta cytokine in Korean patients with gastric cancer

Interleukin-1B and IL-1 receptor antagonist gene polymorphisms are associated with an increased risk of gastric cancer (GC) in Caucasian populations. However, recent studies could not find any association between IL-1B-511T polymorphism and the risk of GC in Asians. We tested for an association between IL-1 loci polymorphisms with increased gastric mucosal levels of IL-1beta and an increased risk of developing GC in a Korean population. Polymorphisms of IL-1A-889, IL-1B-31, IL-1B-511 and IL-1RN were genotyped in 434 controls and 234 patients with GC. Mucosal IL-1beta cytokine was measured using an ELISA. The frequencies of IL-1A, IL-1B-511, IL-1B-31 and IL-1RN were not statistically different between controls and all patients with GC. After subclassification of GC, only patients with intestinal-type GC showed a higher frequency of IL-1B-31T homozygotes (OR = 2.2; 95% CI = 1.1-4.3) compared with controls. Risk was also significantly increased in these patients for IL-1B-31T homozygotes compared with patients with diffuse-type GC (OR = 3.4; 95% CI = 1.5-7.7). As in Caucasian populations, linkage disequilibrium between IL-1B-31 and IL-1B-511 was nearly complete, but the pattern of haplotype related to the risk of GC (IL-1B-31T/IL-1B-511C) was opposite (IL-1B-511T/IL-1B-31C). Mucosal IL-1beta levels in H. pylori-infected GC patients were higher in patients homozygous for IL-1B-31T compared with IL-1B-31C/T and IL-1B-31C/C. Thus, the combined effects of H. pylori infection and IL-1B-31T/IL-1B-511C polymorphisms with enhanced mucosal IL-1beta production contributed to the development of intestinal-type GC in this Korean population.     

Genetic variants in the IL1A gene region contribute to intestinal‐type gastric carcinoma susceptibility in European populations

The most studied genetic susceptibility factors involved in gastric carcinoma (GC) risk are polymorphisms in the inflammation‐linked genes interleukin 1 (IL1) B and IL1RN. Despite the evidence pointing to the IL1 region, definite functional variants reproducible across populations of different genetic background have not been discovered so far. A high density linkage disequilibrium (LD) map of the IL1 gene cluster was established using HapMap to identify haplotype tagSNPs. Eighty‐seven SNPs were genotyped in a Portuguese case‐control study (358 cases, 1,485 controls) for the discovery analysis. A replication study, including a subset of those tagSNPs (43), was performed in an independent analysis (EPIC‐EurGast) containing individuals from 10 European countries (365 cases, 1284 controls). Single SNP and haplotype block associations were determined for GC overall and anatomopathological subtypes. The most robust association was observed for SNP rs17042407, 16Kb upstream of the IL1A gene. Although several other SNP associations were observed, only the inverse association of rs17042407 allele C with GC of the intestinal type was observed in both studies, retaining significance after multiple testing correction (p = 0.0042) in the combined analysis. The haplotype analysis of the IL1A LD block in the combined dataset revealed the association between a common haplotype carrying the rs17042407 variant and GC, particularly of the intestinal type (p = 3.1 × 10^?5) and non cardia localisation (p = 4.6 × 10^?3). These results confirm the association of IL1 gene variants with GC and reveal a novel SNP and haplotypes in the IL1A region associated with intestinal type GC in European populations.     

Association of immunoescape mechanisms with Epstein-Barr virus infection in nasopharyngeal carcinoma

We have investigated the association of immunoescape mechanisms in nasopharyngeal carcinoma (NPC) lesions with Epstein-Barr virus (EBV) infection and clinical course of the disease. Tumor biopsy specimens obtained from 36 Japanese NPC patients were examined for antigen processing machinery component and HLA class I antigen expression, CD8(+) T cell infiltration, and Fas, Fas ligand (FasL) and IL-10 expression using immunohistochemical staining. The results were correlated with the histopathological characteristics of the lesions, the clinical course of the disease and EBV infection. LMP2, TAP1, tapasin and HLA class I antigens were downregulated in more than 65% of the lesions tested, while FasL, Fas and IL-10 were expressed in at least 60% of the lesions. Statistical analysis showed that (i) HLA class I antigen expression was significantly correlated with LMP2 and tapasin expression (r = 0.39 and 0.45, respectively); (ii) CD8(+) T cell infiltration into tumor lesions was significantly correlated with HLA class I antigen, LMP2 and Fas expression (r = 0.34, 0.49 and 0.44, respectively); (iii) LMP2 and FasL expression was significantly correlated with IL-10 expression (r = 0.49 and 0.52, respectively); (iv) IL-10 expression was significantly associated with EBERs and EBV oncoprotein LMP1 expression (p = 0.00078 and 0.015, respectively) and (v) FasL overexpression was significantly associated with reduced patients' survival (p = 0.033). Multivariate analysis identified FasL overexpression as an independent unfavorable prognostic marker. These results suggest that NPC cells may utilize multiple immunoescape mechanisms, including dysfunction of HLA class I antigens and Fas/FasL apoptosis pathways. Furthermore, FasL expression appears to be associated with IL-10 upregulation in EBV positive NPC cells.     

ASSOCIATION OF pIgR POLYMORPHISMS WITH NASOPHARYNGEAL CARCINOMA

Objective： Epstein-Barr virus （EBV） associated nasopharyngeal carcinoma （NPC） is an important squamous cell cancer endemic in southern China and Southeast Asia. pIgR （polymeric immunoglobulin receptor） gene plays central roles during immune responses and EBV inflammatory and therefore is a good candidate susceptibility gene for NPC. This study is to evaluated potential associations between pIgR gene and NPC susceptibility. Methods： Sequencing was used to identify multiple single nucleotide polymorphisms （SNPs） within the exon regions of pIgR in Guangdong population. Four SNPs were genotyped in 528 NPC patients and 408 normal individuals to perform case-control study. Results： There was no statistical difference in the allele frequencies of each SNP （P〉0.05）. After categorized into 2 groups by age of 45 y, in the group of age below 45 the minor allele T frequency of C888oT was 7%, whereas 4% in controls, with significant difference （P〈0.05）. The Odds Ratio （OR=1.84） also showed higher risk of NPC with individuals carried the minor alleles. Conclusion： The result has proved that SNP C8880T is associated with NPC susceptibility and pIgR gene might play a certain role in oncogenesis and development of NPC.     

骨肉瘤易感性与相关基因多态性的研究进展

骨肉瘤是一种好发于青少年肱骨干骺端、胫骨近端和股骨远端的原发性恶性骨肿瘤。虽然手术联合化疗的综合治疗将骨肉瘤患者的5年生存率从30％提高至50％～70％,但其易复发且易发生转移,骨肉瘤的致残率和死亡率依然很高。大量研究资料显示,骨肉瘤的发病机制除了与环境因素有关外,还与遗传因素密切相关。其中,基因多态性是遗传因素中的重要组成部分,参与疾病的发生与发展。目前,关于骨肉瘤易感性相关基因多态性的研究已很多,并取得一定的成就,均是致力于骨肉瘤的预防、诊断、治疗及判断预后。本文就近年来关于骨肉瘤易感性与相关基因多态性的研究进展做一综述。     

谷胱甘肽硫转移酶M1基因编码区多态性与中国南方人群鼻咽癌易感性的关系

背景与目的：研究发现谷胱甘肽硫转移酶M1（glutathione S-tranferase M1,GSTM1）基因缺失可使患鼻咽癌的危险性增加。本研究旨在通过对GSTM1基因编码区单核苷酸多态（single nucleotide polymorphism,SNP）位点的研究,来评估其与中国南方人群鼻咽癌遗传易感性的关系。方法：239例鼻咽癌患者和286例健康人群入组该实验、其中225例鼻叫癌患者及273例对照的实验结果用于统计学分析。在GSTM1基因外显子区、内含子和外显子交界区设计引物,用PCR产物直接测序（测序总长度4739bp）,从中获得SNP位点。选择编码区多态位点T1270533G和C1256088C,用tetra—PFimerARMS—PCR和测序方法进行病例．对照研究。结果：通过测序共获取29个SNPs编码区。T1270533G和C1256088C位点氨基酸的密码子分别发生了碱基颠换,产生了错义突变。对225例鼻咽癌患者和273例健康人群分型结果表明T1270533G位点的变异与鼻咽癌临床表型之间无明显关联（OR=0．170,纯合子TT95％CI=0．95—0．306）。C1256088C位点缺失率在鼻咽癌人群中为45％（45／100）,在对照人群中为42％（42／100）。结论：编码区T1270533G位点的多态性并没有影响该基因的解毒功能。该位点与中国南方人群鼻咽癌遗传易感性无明显关联。本组多态性位点C1256088C缺失率高。     

Identification of serum biomarkers for nasopharyngeal carcinoma by proteomic analysis

BACKGROUND: Early diagnosis of nasopharyngeal carcinoma (NPC) remains a challenge. Serum protein profiling is a promising approach for the classification of cancer versus noncancer samples. The objective of the current study was to assess the feasibility of mass spectrometry-based protein profiling and a classification tree algorithm for discriminating between patients with NPC and noncancer controls. METHODS: Serum samples from patients with NPC and noncancer controls were analyzed by using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). The study was divided into a preliminary training set and a blind test set: A preliminary training set and a classification tree of spectra derived from 55 patients with NPC and a group of 60 noncancer controls were used to develop a proteomic model that discriminated cancer from noncancer effectively. Then, the validity of the classification tree was challenged with a blind test set, which included another 25 patients with NPC and 28 noncancer controls. RESULTS: Four protein peaks at 4097 daltons (Da), 4180 Da, 5912 Da, and 8295 Da were chosen automatically as a biomarker pattern in the training set that discriminated cancer from noncancer with sensitivity of 94.5% and specificity of 96.7%. When the SELDI marker pattern was tested with the blinded test set, it yielded a sensitivity of 92%, a specificity of 92.9%, and an accuracy rate of 92.5%. The accuracy of 2 protein peaks (4581 Da and 7802 Da) was 80% for predicting stage I and II NPC and 86% for predicting stage III and IV NPC. CONCLUSIONS: The high sensitivity and specificity obtained by the serum protein profiling approach demonstrated that SELDI-TOF-MS combined with a tree analysis model both can facilitate discriminating between NPC and noncancer controls and can provide an innovative clinical diagnostic platform to improve the detection of NPC.     

Upregulated claudin‐1 expression confers resistance to cell death of nasopharyngeal carcinoma cells

Accumulating evidence reveals that aberrant expression of claudins manifests in various tumors; however, their biological functions are poorly understood. Here, we report on the elevated expression of claudin‐1 in nasopharyngeal carcinoma (NPC) cell lines under serum deprivation or fluorouracil (5‐FU) treatment. Interestingly, an increase in expression of claudin‐1 considerably reduced apoptosis rather than enhancing cell proliferation. However, claudin‐1 expression and activity were unaffected by external stimuli or Akt and NF‐κB activation. Notably, predominant cytoplasmic and nuclear localization of claudin‐1 in NPC cells reflected the aforementioned feature. On the other hand, loss of epithelial morphology and E‐cadherin expression was associated with serum withdrawal in NPC cells. Interestingly, restoration of E‐cadherin inhibited the protein elevation and antiapoptotic activity of claudin‐1. In conclusion, our data demonstrate the regulation and novel biological function of claudin‐1 and indicate the important role of claudin‐1 in NPC tumorigenesis.     

细胞色素P4502E1基因与鼻咽癌易感性分析

目的：为了探讨鼻咽癌的病因发病机理,进一步揭示鼻咽癌的易感因素,本文进行了细胞色素Ｐ４５０２Ｅ１（ＣＹＰ２Ｅ１） 基因多态性与鼻咽癌易感性关系的研究。方法：采用病例－ 对照分子流行病学方法分析１０５ 例鼻咽癌患者和９３ 例正常人体细胞ＣＹＰ２Ｅ１ 基因型。结果： 发现ＲｓａＩ和ＰｓｔＩ识别的ＣＹＰ２Ｅ１ 基因纯合子突变型（Ｃ２／Ｃ２） 在鼻咽癌人群为５－７ ％ ,显著高于正常人群（１－１％ ） 分布（χ２ ＝ ４－８６ ,Ｐ＜ ０－０５） ;携带Ｃ２／Ｃ２ 基因型个体发生鼻咽癌的危险性比携带其它基因型个体高５ 倍左右。结论：ＣＹＰ２Ｅ１ 基因的多态性可能是鼻咽癌易感的因素之一。     

红细胞补体受体1单核苷酸多态性与肝细胞癌发病风险的研究

目的 探讨红细胞补体受体1（CR1）单核苷酸多态性（SNP）与肝细胞癌（HCC）发病的关系。方法 收集102例HCC患者（HCC组）和98例健康体检者（对照组）的外周血样本,选取CR1的5个标签SNP位点（rs4844600 G＞A、rs17048010 T＞C、rs3818361 C＞T、rs11118167 T＞C和rs9429945 C＞T）进行检测,分析两组的红细胞CR1基因各SNP位点基因型、等位基因及单体型的分布差异及其与HCC患病风险的关系。同时按照性别、年龄相匹配的原则分别从对照组和HCC组中选取52例和53例样本采用流式细胞术检测其红细胞CR1的几何平均荧光强度比值（GMFIR）。结果 两组rs4844600 G＞A基因型和等位基因分布的差异有统计学意义（P＜0.01）。CR1基因rs4844600 G＞A／GG基因型携带者患HCC的风险为非携带者的2.458倍（95％ CI：1.357～4.451）,GA基因型携带者患病风险是非携带者的0.404倍（95％CI：0.218～0.746）,其等位基因G携带者患病风险为非携带者的1.945倍（95％CI：1.183～3.199）。rs17048010 T＞C、rs3818361 C＞T、rs11118167 T＞C、rs9429945 C＞T这4个SNP位点和rs11118167-rs3818361-rs17048010／TCT、TTC、CCT、TTT这4种单体型与HCC的患病风险无关（P＞0.05）。HCC组CR1的GMFIR水平为3.257±1.191,高于HCC组的2.652±0.789,差异有统计学意义（t=2.644,P=0.008）。结论 HCC患者红细胞免疫功能降低,CR1基因SNP位点rs4844600 G＞A与HCC发病关联。     

Epstein-Barr virus seroreactivity among unaffected individuals within high-risk nasopharyngeal carcinoma families in Taiwan

Most adults have been infected with EBV. Many studies have indicated that antibodies against specific EBV antigens, particularly IgA antibodies, can be predictive or prognostic of EBV-associated malignancies, such as NPC. We hypothesized that healthy individuals from families with a history of multiple members affected with NPC (who therefore might be genetically susceptible to NPC themselves) might have an EBV antibody profile that is distinct from that seen in healthy individuals from the community at large. To explore this possibility and examine determinants of anti-EBV antibody levels in healthy, high-risk individuals, we evaluated data from 2 parallel studies of NPC in Taiwan, which included 1,229 healthy members of families in which 2 or more individuals were affected with NPC and 320 controls from the community at large. Blood collected from participants was tested for IgA antibodies against EBV VCA and EBNA-1 and for neutralizing antibodies against EBV DNase using standard assays. We observed evidence of familial aggregation of EBV seroreactivity among individuals from high-risk, multiplex NPC families. Anti-VCA IgA and anti-EBNA-1 IgA antibody seroprevalence in unaffected family members of NPC cases was 5-6 times higher than in members of the community (p < 0.01). This elevated seroprevalence among unaffected individuals from high-risk families was observed regardless of the relationship of the unaffected individual to the closest affected relative (siblings, parents, children or spouses). No sociodemographic or environmental factors examined were found to strongly and consistently correlate with elevated seroprevalence, but patterns emerged of increasing seroprevalence among older individuals and among females. Unaffected individuals from high-risk NPC families have elevated anti-EBV IgA antibody titers. The etiologic and clinical implications of this finding remain to be established.     

ERCC1基因多态性与食管癌的研究进展

核苷酸切除修复交叉互补基因1(excision repair cross complementation 1,ERCC1)是核苷酸切除修复(NER)系统的关键酶,其表达情况与食管癌的发生发展及铂类耐药有关.检测ERCC1基因多态性有助于制定食管癌个体化治疗.     

miR-146a 多态性与非小细胞肺癌易感性的研究

目的：研究汉族人群miR-146a rs2910164 G/C基因多态性与非小细胞肺癌易感性的关系。方法：通过病例-对照研究,应用PCR-限制性片段长度多态性（PCR-RFLP）检测技术对198例非小细胞肺癌患者与218例对照组人群进行rs2910164基因型的检测,并随机抽取10%的样本进行DNA测序,进行遗传平衡检测。进一步采用Logistic回归分析该位点与非小细胞肺癌的相关性。结果：rs2910164被酶切成GG、GC、CC基因型,GG、GC、CC分型在对照组分别为103例（47.25%）、85例（38.99%）、30例（13.76%）;在病例组分别为31例（15.66%）、99例（50.00%）、68例（34.34%）。随机抽取10%的样本进行DNA测序,其结果与PCRRFLP分型结果一致,基因分型频率满足Hardy-Weinberg遗传平衡（P>0.05）。与对照组相比,Logistic回归分析发现携带C等位基因的基因型可明显增加非小细胞肺癌的发病风险[显性模型OR=5.04,95%CI为（4.72,5.39）,P<0.01;隐性模型OR=2.75,95%CI为（2.57,2.94）,P<0.01];而rs2910164基因多态性与非小细胞肺癌的临床病理特征（分级、分期、转移）之间无明显相关关系（P>0.05）,rs2910164基因多态性与吸烟之间无交互作用（P>0.05）。结论：携带miR-146a rs2910164 C等位基因的基因型可能与非小细胞肺癌的遗传易感性相关。     

鼻咽癌患者血清MTA1浓度与临床特征及预后的关系

目的:本研究旨在检测鼻咽癌患者治疗前血清中MTA1的水平,探讨其与临床特征及预后的关系。方法:收集2011年3月至2015年4月在我院治疗的初诊无转移鼻咽癌患者96例的临床资料及治疗前血清标本。利用ELISA方法测定血清MTA1浓度,以中位浓度为截断值,将患者分为低表达组和高表达组,采用单因素和多因素方法分析治疗前患者血清中MTA1浓度与临床病理特征及生存率的关系。结果:全组患者血清MTA1中位浓度为112 pg/ml（0~8 215 pg/ml）,中位随访47个月,23例患者发生远处转移,治疗前MTA1水平与远处转移相关（P=0.031）,但与性别、年龄、T、N分期及临床分期均无关。生存率分析显示,MTA1高表达组4年DMFS为73.2%,显著低于MTA1低表达组的86.7%（P=0.039）;MTA1高表达组与低表达组患者4年PFS分别为 70.8%和87.3%,趋向于有统计学意义（P=0.054）;尽管MTA1高表达患者4年OS低于MTA1低表达患者,但差异无显著统计学意义（82.1% vs 86.9%,P=0.091）。多因素分析表明:治疗前患者血清MTA1表达水平并不是鼻咽癌患者OS、PFS及DMFS的独立预后因素（P=0.349、P=0.126、P=0.106）。结论:鼻咽癌患者治疗前血清MTA1高表达与无转移生存相关。     

Functional NBS1 polymorphism is associated with occurrence and advanced disease status of nasopharyngeal carcinoma

As a component of the MRN (MRE11/RAD50/NBS1) complex, NBS1 plays an important role in cellular response to DNA damage and the maintenance of chromosomal integrity. The NBS1 E185Q polymorphism (8360G>C, rs1805794) has been frequently studied in some cancers with discordant results, but its association with nasopharyngeal carcinoma (NPC) in Chinese population has not been investigated. Moreover, there is no report about the association between NBS1 3'UTR variant rs2735383 and the risk of NPC. A multiple center case-control analysis was performed to assess the association between NBS1 polymorphisms and NPC risk in Eastern and Southern Chinese population. The genotypes and haplotypes were determined in 1052 cases and 1168 controls and the associations with risk of NPC were estimated by logistic regression. Cell migration assays were performed in 24-well transwell chambers to detect the effects of NBS1 E185Q SNP on cell migration. We observed significant difference in genotype frequencies at the rs1805794 C/G site between cases and controls (P(trend) < 0.0001). The C allele increases the risk for invasive disease or metastatic disease, compared with G allele. More over, CNE-2 cells (NPC cell line) transfected with pcDNA-NBS1-185Q (8360CC) had significantly higher migration levels than those transfected with pcDNA-NBS1-185E (8360GG) (P = 0.024). These findings suggest that E185Q polymorphism in NBS1 may be a genetic modifier for the occurrence and aggression of NPC.