单核苷酸多态与乳腺癌治疗反应相关研究进展

单核苷酸多态(SNP)指基因组DNA序列中频率大于1%的单核苷酸变异。这种变异有时导致其编码不同的蛋白从而引起生物学特征的变化,在乳腺癌的治疗上表现为不同患者出现不同的治疗反应和毒性。研究不同基因的SNP与乳腺癌治疗反应的相关性可以为实现乳腺癌个体化治疗提供坚实的理论基础。     

淋巴细胞弱化因子基因多态性与乳腺癌发病风险研究

目的:探讨B及T淋巴细胞弱化因子(B and T Lymphocyte attenuator,BTLA)SNP位点在黑龙江省妇女乳腺癌患者及正常对照人群中的基因型和等位基因频率;确定BTLA基因与黑龙江省妇女乳腺癌发病风险的相关性.方法:抽取280例乳腺癌患者及262例健康女性外周血5mL,试剂盒提取DNA后.利用聚合酶链式反应限制性片段长度多态性(polymerase chain reaction restriction fragment length polymorphism,PCR-RFLP)技术进行BTLA基因外显子及内含子的SNP位点DNA扩增,检测BTLA基因位点多态性,分析患者与正常对照差别,进而确定该基因与黑龙江省妇女乳腺癌的相关性.结果:乳腺癌患者的BTLA基因外显子及内含子中杂合子基因型高于正常对照者,有统计学差异(P＜0.05,OR>1.00),内含子中rs2705535 GG基因型乳腺癌患者组中的基因频率低于正常对照组(P＜0.05,OR<1.00).A等位基因在乳腺癌患者中频率高于正常对照组(P＜0.05,OR>1.00).具有统计学意义.结论:BT-LA基因多态性与黑龙江省妇女乳腺癌发病风险存在一定关联性.     

TNRC9和FGFR2基因多态性与湖北地区汉族人群乳腺癌患病风险研究

目的:研究探讨TNRC9基因rs3803662和FGFR2基因rs17102287单核苷酸多态性(SNP)及两SNP连锁与湖北地区汉族妇女乳腺癌易感性的关系.方法:抽取汉族510例乳腺癌患者和550例健康妇女外周血,分离淋巴细胞,抽提基因组DNA,检测TNRC9 rs3803662和FGFR2 rs17102287 的基因多态性,计算基因型和等位基因频率,研究各基因型以及基因SNP连锁之间对乳腺癌风险的影响.结果:TNRC9基因SNP位点rs3803662的C/C、C/T和T/T基因型频率在病例组和对照组分别为13.0％、46.4％、40.6％和7.3％、52.1％、40.6％,其基因型频率相比差异有统计学意义,x2=9.40,P=0.043.而等位基因频率两组相比差异均无统计学意义;FGFR2基因SNP位点rs17102287的C/C、C/T和T/T基因型频率在病例组和对照组中差异无统计学意义;等位基因频率两组相比差异无统计学意义.两基因连锁分析D'=0.087,r2=0.085,没有明显连锁不平衡现.结论:TNRC9基因rs3803662多态性与汉族妇女乳腺癌易感性有关,FGFR2基因rs17102287多态性及其与TNRC9基因rs3803662单倍体连锁与湖北地区汉族人群妇女乳腺癌易感性无相关性.     

单核苷酸多态性与肺癌化疗疗效及预后相关研究进展

单核苷酸多态性（single nucleotide polymorphism，SNP），指基因组DNA序列中频率大于1％的单个核苷酸的变异，这种变异有时导致其编码的蛋白结构和功能发生改变，从而影响其生物学功能。在肿瘤治疗领域表现为不同SNP基因型患者对治疗发生不同的反应．目前SNP与非小细胞肺癌疗效相关研究的主要基因包括DNA切除修复基因、基质金属蛋白酶基因、凋亡相关基因、药物代谢相关基因、细胞周期渊控綦因等。我们就SNP与肺癌化疗的疗效以及预后的相关性进行了综述。     

利用单核苷酸多态性芯片全基因组检测人大细胞肺癌细胞株的杂合性缺失和拷贝数变异

背景和目的DNA序列的杂合性缺失(LOH)和拷贝数变异(CNV)普遍存在于肿瘤基因组,并认为与肿瘤发生发展相关。高密度单核苷酸多态性(SNP)芯片能够检测全基因组的LOH和CNV适用于研究肿瘤遗传变异。本研究运用该技术寻找人大细胞肺癌细胞株NL9980全基因组的LOH和CNV。方法提取细胞株总DNA并应用500K SNP芯片进行检测。芯片获得的500000位点的杂交信号强度数据使用Affymetrix专利软件估算各SNP位点基因型和拷贝数。进一步分析获得NL9980全基因组LOH和CNV。结果芯片的SNP位点检测率超过了93%的主要质控标准。NL9980细胞中LOH散布在所有染色体,CNV主要分布在2,3,4,5,7,10,11和18号等染色体。结论研究表明NL9980基因组存在复杂的遗传变异。SNP芯片高分辨率和提供等位基因型信息等优势极大地提高了肺癌遗传变异研究的能力。     

DNA甲基化与乳腺癌

DNA甲基化是人类基因组发生的最为常见的一种表观遗传学事件,在乳腺癌发生相关机制中具有重要意义.本文主要对乳腺癌肿瘤细胞内DNA甲基化异常、DNA甲基化及其与乳腺癌诊治和预后判断的研究进展作一综述,并对去甲基化治疗的前景进行展望.     

BRCA1相关A蛋白复合物基因单核苷酸多态性与三阴性乳腺癌易感性研究

背景与目的：BRCA1突变与三阴性乳腺癌发病相关目前已得到学者公认。该研究旨在分析BRCA1相关A蛋白复合物相关基因的单核苷酸多态性(single nucleotide polymorphisms,SNP)与三阴性乳腺癌发病风险的关系,寻找和确定与汉族人群三阴性乳腺癌遗传易感性相关的基因型和单体型。方法：2008年-2011年间414例在复旦大学附属肿瘤医院接受原发性乳腺癌手术的三阴性乳腺癌患者和354例健康妇女进入本病例对照研究。通过对Abraxas、BRE、Rap80、NBA1和BRCC36基因组DNA的37个SNP位点的检测,分析它们与三阴性乳腺癌的相关性。研究者随后检测了652例其他类型乳腺癌和890例健康女性的DNA以证实发现的SNP是否为三阴性特有的遗传相关位点。结果：该研究在第一步研究中发现,NBA1启动子区rs7250266位点突变的G等位基因在三阴性乳腺癌患者中的频率显著低于在正常女性中的频率(0.14 vs 0.19,P<0.01)。对rs7250266位点基因分型显示：与携带CC基因型个体比较,携带GC型个体的三阴性乳腺癌的发病风险显著降低(GC∶OR=0.70,95%CI：0.51~0.97;GG∶OR=0.48,95%CI：0.21~1.07,P=0.03)。单体型分析也证实NBA1基因的不同单体型间三阴性乳腺癌发病风险不同。第二步的研究结果显示,rs7250266位点突变在非三阴性的乳腺癌与正常人群中差异无统计学意义(0.19 vs 0.18,P=0.85)。结论：NBA1基因的rs7250266位点的单核苷酸多态性与汉族女性的三阴性乳腺癌发病风险相关,其突变型等位基因携带者罹患三阴性乳腺癌的风险低于野生型等位基因携带者。     

MDM2基因SNP309可能与早发性乳腺癌易感性无关:福建病例-对照研究

背景与目的:MDM2基因是p53基因的负性调控因子,其SNP309遗传多态性可能与乳腺癌发病风险有关,本研究探讨SNP309多态性在福建早发性乳腺癌人群中的分布及其与乳腺癌发病风险的相关性.方法:对123例早发性乳腺癌患者(发病年龄≤35岁)和101例正常对照者进行MDM2基因SNP309(T>G,rs2279744)的PCR扩增,并采用时间飞行质谱分析(MALDI-TOF-MS)法鉴定多态性的基因型,比较基因型分布和发病风险的关系;危险度OR及95%CI应用非条件Logistic回归分析计算.结果:MDM2基因SNP309多态性基因型在正常对照组和病例组中的分布频率分别为TT:28(27.7%)/26(21.1%),TG:50(49.5%)/61(49.6%),GG:23(22.8%)/36(29.3%);两组间分布频率差异无统计学意义(P>0.05).Logistic回归分析表明,在早发性乳腺癌人群中,以rs2279744的TT基因型为参照,含G基因型(TG,GG)未显著性地提高乳腺癌的发病危险,OR=1.358(95%CI:0.706～2.614,P>0.05).结论:MDM2基因SNP309(T>G,rs2279744)多态性可能与福建地区汉族人群早发性乳腺癌的遗传易感性无关,其作为低外显率的乳腺癌易感基因位点尚不明确,作为未来临床基因筛查的候选指标还需谨慎.     

MDM2基因SNP309多态性与宫颈癌的相关性研究

目的:研究汉族妇女中MDM2基因SNP309多态性与宫颈癌易感性及临床病理学参数之间的关系.方法:用DNA抽提试剂盒从研究对象的外周血标本中抽提基因组DNA,其中宫颈癌患者105例,正常对照组140例;用聚合酶链式反应-限制性片段长度多态(PCR-RFLP)和直接测序方法测定MDM2-SNP309单核苷酸多态基因型.结果:宫颈癌患者的MDM-SNP309G等位基因频率显著高于对照组(60.0% vs 48.6%,P=0.012;OR=1.59,95%CI=1.11～2.28);宫颈癌与对照组之间的GG、TG和TT等位基因型的分布差异有统计学意义,其中GG等位基因型在宫颈细胞癌中的频率显著高于对照组(36.2%vs 18.6%,P=0.016;OR=2.58,95%CI=1.19～5.61).在宫颈癌组中,淋巴转移阳性组MDM2-SNP309 CG等位基因型显著高于淋巴转移阴性组(31.8% vs11.5%,P＜0.05),SNP309单核苷酸多态性分布与肿瘤组织学类型、病理分级及肿瘤大小无关.结论:MDM2基因SNP309GG基因型是宫颈癌发生的遗传易感因素,与宫颈癌的淋巴转移发生有相关性.     

湖北地区人群乳腺癌易感基因FGFR2多态性研究

目的:探讨湖北地区人群成纤维细胞生长因子受体-2基因(FGFR2)第2内含子单核苷酸多态性(SNP)与乳腺癌易感性的关系。方法:采用PCR及DNA测序方法,对汉族204例女性乳腺癌患者(乳腺癌组)和192名正常女性(对照组)FGFR2基因第2内含子区的2个多态性位点(rs2981582和rs10510097)进行分析,计算基因型和等位基因频率。结果:汉族人群正常对照组FGFR2基因第2内含子SNP位点rs2981582的C/C、C/T和T/T基因型频率分别为31.82%、54.54%和13.64%,而乳腺癌组分别为34.02%、53.61%和12.37%,其基因型和等位基因频率两组相比差异均无统计学意义,P值均>0.05;另一位点rs10510097正常对照组的C/C、C/T和T/T基因型频率分别为60.00%、33.33%和6.67%,乳腺癌组分别为55.31%、36.87%和7.82%,其基因型和等位基因频率两组相比差异均无统计学意义,P值均>0.05。结论:湖北地区人群FGFR2第2内含子2个多态性位点和乳腺癌并无明显相关性。     

DNA修复基因单核苷酸多态性预测铂类药物敏感性和预后

铂类药物是治疗实体肿瘤常用的药物之一,但是肿瘤细胞对铂类药物耐药导致化疗失败,成为临床治疗的一大难题。DNA修复能力是影响疗效的重要原因。DNA修复基因单核苷酸多态性(SNP)可改变DNA修复能力,因此,检测这些基因的单核苷酸多态性可以预测疗效。现综述DNA修复基因单核苷酸多态性预测铂类药物敏感性和预后的研究进展。     

Host immune gene polymorphisms were associated with the prognosis of non-small-cell lung cancer in Chinese

Laboratory-based studies showed that host immune genes could influence the prognosis of non-small-cell lung cancer (NSCLC). Therefore, genetic polymorphisms in host immune genes may serve as predictors for NSCLC clinical outcome. To test the hypothesis that functional single nucleotide polymorphisms (SNPs) in host immune genes are associated with the prognosis of NSCLC, we systematically performed a genotyping analysis for a total of 178 SNPs from 52 immune genes in a prospective case cohort of 568 NSCLC patients. Among the 178 SNPs, 24 were significantly associated with NSCLC prognosis in different genetic models and four of them were remained in the final predictive model after multivariate stepwise Cox regression, including IL-5R rs11713419 (5'-untranslated region, 5'-UTR) (P = 0.001), IL23R rs6682925 (5'-flanking region, 5'-FR) (P = 0.017), TLR1 rs5743551 (5'-FR) (P = 0.02) and TLR3 rs3775291 (Leu412Phe) (P = 0.01). We then put the above four SNPs together, and found that the risk of death was significantly increased by 124% (HR = 2.24, 95% CI: 1.33-3.75) for the patients carrying "1" unfavorable locus and by 175% (HR = 2.75, 95% CI: 1.67-4.51) for those carrying "2-4" unfavorable loci. The risk score model and time-dependent ROC analyses further support the four SNPs and clinical risk score model. The area under curve (AUC) at year 5 increased from 0.484 to 0.831 after combining the four SNPs risk score with clinical risk score. These findings indicate that potentially functional polymorphisms in immune genes may serve as prognostic markers of clinical outcome of NSCLC.     

Linkage disequilibrium pattern in the L-myc gene in Italian and Japanese non-small-cell lung-cancer patients

Italian and Japanese non-small-cell lung-cancer patients were genotyped for an intragenic L-myc EcoRI restriction site polymorphism previously reported to be associated with lung-tumor prognosis in Asian populations but not in Caucasians. Screening of the L-myc sequence in Italian samples allowed identification of 2 additional 3'-UTR SNPs, located 2.3-3.0 kb from the EcoRI polymorphism, but no coding polymorphism was found. No significant association was found between any of the 3 SNPs and lung-tumor prognosis in Italian patients, consistent with the reported difference between Caucasian and Asian populations. Moreover, the newly discovered polymorphisms in the Italian group were not present in Japanese patients. Significant LD between EcoRI and the 2 other SNPs was detected in the Italian population, whereas no significant LD between the 2 3'-UTR markers was detected despite their close proximity (0.7 kb). Thus, the disparate conclusions about the role of L-myc polymorphism in tumor prognosis among different populations may rest in population-specific LD between the functional gene and the L-myc polymorphism.     

Association between genetic variations in tumor necrosis factor receptor genes and survival of patients with T-cell lymphoma

The prognosis of T-cell lymphoma (TCL) has been shown to be associated with the clinical characteristics of patients. However, there is little knowledge of whether genetic variations also affect the prognosis of TCL. This study investigated the associations between single nucleotide polymorphisms(SNPs) in tumor necrosis factor receptor superfamily(TNFRSF) genes and the survival of patients with TCL. A total of 38 tag SNPs in 18 TNFRSF genes were genotyped using Sequenom platform in 150 patients with TCL. Kaplan-Meier survival estimates were plotted and significance was assessed using log-rank tests. Cox proportional hazard models were used to analyze each of these 38 SNPs with adjustment for covariates that might influence patient survival, including sex and international prognostic Index score. Hazard ratios (HRs) and their 95% confidence intervals(CIs) were calculated. Among the 38 SNPs tested, 3 were significantly associated with the survival of patients with TCL. These SNPs were located at LTβR (rs3759333CT) and TNFRSF17(rs2017662CT and rs2071336CT). The 5-year survival rates were significantly different among patients carrying different genotypes and the HRs for death between the different genotypes ranged from 0.45 to 2.46. These findings suggest that the SNPs in TNFRSF genes might be important determinants for the survival of TCL patients.     

单核苷酸多态性与小细胞肺癌的研究进展

目的:基于目前多种基因的单核苷酸多态性(SNPs)在小细胞肺癌(SCLC)中的研究进展,进一步探讨基因的SNPs对SCLC易感性、化疗疗效及预后的影响.方法:应用PubMed和万方期刊全文检索系统,以“小细胞肺癌,单核苷酸多态性”等为关键词,检索2006-2011年发表的相关文献.共检索到258文献条.纳入标准:1)SNPs与SCLC易感性;2)SNPs与SCLC化疗疗效;3)SNPs与SCLC预后.根据纳入标准,共纳入分析文献39篇.结果:单核苷酸多态性是第3代分子遗传标志,SNPs决定基因的功能单位和人群遗传变异的内在特征,它反映了个体表型、疾病易感性和对药物、环境因子反应的差异.近年来国内外许多学者研究表明,许多基因位点的SNPs与SCLC的易感性、化疗疗效及预后相关,这些SNPs主要发生于DNA修复基因、致癌物质代谢基因、癌基因、抑癌基因、凋亡相关基因和药物代谢相关基因等.随着第2代高通量测序方法的应用,不仅能对高频和低频乃至稀有变异进行检测,还能发现新的突变位点,将在一定程度上推动SNPs的研究.结论:SNPs在SCLC的易感性、化疗疗效及预后的研究中发挥着潜在的重要的作用.     

Patient Profiling for Treatment Toxicity: Potential Use of Clinical and Genomic Factors

Significant advances have been made in the identification of genes associated with the occurrence and prognosis of a variety of cancers. Recent efforts have also identified specific genomic single nucleotide polymorphisms (SNPs) that are associated with treatment toxicity in oncology, including toxicity associated with irinotecan, 5-FU, and 6-mercaptopurine. Despite the identification of these potential genomic predictors, their clinical use has been limited. Recent work has identified combined clinical characteristics and SNPs associated with toxicity with temozolomide. This combined approach may allow for identification of those at risk, and by using clinical parameters for screening, further refine those who require the more expensive genomic testing. This approach, as well as evaluation of clinical utility, economic impact, and ease of use are important components necessary for evaluation and use of genomic predictors of toxicity in the future.     

胃癌差异表达miRNA及其相关基因的单核苷酸多态性与胃癌预后的相关性研究

目的：探讨胃癌差异表达微小RNA（miRNA）及其相关基因的单核苷酸多态性（SNPs）与胃癌预后的相关性，为进一步寻找胃癌预后的生物标志物提供线索。方法：应用SNP芯片联合生物信息学分析对福建省胃癌高发区仙游县96例胃腺癌患者与96例健康对照人群基因组中miRNA及其相关基因的SNPs位点进行筛检，应用飞行时间质谱生物芯片（Sequenom MassARRAY）在344例胃癌患者中对筛检出来的SNPs位点进行检测。开展现场流行病学调查，通过面对面的访谈及问卷调查取得患者的病情、治疗方法、患病后1年的生活饮食习惯，分析其预后情况。结果：共筛检出11个miRNA及其相关基因的SNPs位点，包括5个miRNA自身SNPs、5个miRNA靶序列SNPs以及1个miRNA生物合成通路基因相关SNPs。单因素分析显示miR-1297 rs9536676、MSH2 rs17502941位点的多态性与胃癌预后有关联性，其余的多态性位点均与胃癌预后无明显相关性。多因素分析显示是否手术、TNM分期、rs17502941 AA/AG基因型均是影响胃癌预后的独立危险因素。按年龄TNM分期联合分层得出，miR-1297 rs9536676、miRNA-519b rs10413288、miR-379 rs7143252、FAS基因rs1468063、EGFR基因rs10277413位点均与胃癌患者的生存分布有关联。联合作用分析结果显示患者同时携带rs9536676 AA/AG和rs17502941 GG、rs9536676 AA/AG和rs10413288 AA、rs17502941 GG和rs10413288 AA基因型可能会增加预后不良的风险（P < 0.05）。结论：胃癌差异表达miRNA及其相关基因的SNPs与胃癌病人预后密切相关，可能作为判断胃癌预后的生物标志物。     

结直肠癌中miRNA基因及其靶基因多态性位点的研究进展

结直肠癌是最常见的消化系统肿瘤之一。近年来的研究表明,miRNA在结直肠癌的发病过程起着重要的作用。由于单核苷酸多态性（SNPs）的存在,miRNA的结构和功能可能发生变化,从而影响结直肠癌的发病率。目前国内外对miRNA及其靶基因多态性与结直肠癌的关系研究不多。在本文中,我们将对结直肠癌中miRNA表达谱的改变、miRNA基因及其靶基因多态性与结直肠癌的关系及miRNA基因多态性对于结直肠癌的诊断、预后判断、预测疗效的应用前景等内容进行综述。