PD-L1基因多态性与结直肠癌患者奥沙利铂化疗疗效和安全性的相关性研究

目的:研究PD-L1/3'-UTR上单核苷酸多态性rs4143815与结直肠癌患者奥沙利铂化疗疗效及安全性的相关性。方法:首先,测定262例接受奥沙利铂化疗的结直肠癌患者rs4143815的基因型;然后,统计分析基因型与奥沙利铂化疗疗效、不良反应发生情况及临床病理参数的相关性。结果:PD-L1/3'-UTR上单核苷酸多态性rs4143815与奥沙利铂治疗的疗效显著相关(P=0.028);与C/C型相比,C/G型患者的化疗疗效更好(OR=2.10),而G/G型患者的疗效却更差(OR=0.49)。然而,G/G型患者的不良反应发生率更低(OR=0.46)。此外,PD-L1/3'-UTR上单核苷酸多态性rs4143815与结直肠癌的肿瘤大小显著相关,G/G型患者的肿瘤体积比C/C型患者更小(R=0.08)。结论:rs4143815与奥沙利铂治疗结直肠癌患者的疗效、安全性和肿瘤大小显著相关,可能成为预测结直肠癌患者奥沙利铂治疗的疗效和安全性的参考分子标志物。     

替吉奥联合奥沙利铂及多西紫杉醇治疗晚期胃癌的临床疗效和安全性评估

目的:观察替吉奥联合奥沙利铂及多西紫杉醇治疗晚期胃癌的近期疗效,并对其用药安全性进行评估。方法:选取2010年8月—2012年8月在我院接受治疗的晚期胃癌患者68例,随机分为对照组和观察组,每组34例。对照组患者采取5-FU+奥沙利铂+多西紫杉醇进行治疗,而观察组患者给予替吉奥+奥沙利铂+多西紫杉醇进行治疗,比较两组患者接受不同药物治疗所得到的近期疗效及不良反应的发生情况。结果:观察组治疗的总有效率为58.82%,而对照组治疗的总有效率为32.35%,观察组明显高于对照组,差异显著,具有统计学意义(P0.05);观察组患者治疗后的不良反应发生率为8.82%,而对照组患者治疗后的不良反应发生率为32.35%,观察组明显低于对照组,差异显著,具有统计学意义(P0.05)。结论:替吉奥联合奥沙利铂及多西紫杉醇治疗晚期胃癌疗效显著,不良反应少,患者耐受良好,值得进一步推广和应用。     

XPA 及XPG 基因多态性与晚期非小细胞肺癌铂类药物化疗疗效及 预后的关系

目的:研究DNA修复基因XPAA23G及XPGC46T位点基因多态性与晚期非小细胞肺癌铂类化疗疗效及预后的关系。方法:经病理学确诊的晚期非小细胞肺癌患者89例,化疗前提取其外周血DNA,用DNA测序技术检测XPA、XPG基因型,所有患者均接受2-4个周期铂类药物为基础的化疗。结果:1)89例患者中,携带XPA23A/A及A/G+G/G基因型的化疗有效率分别为47.5%和24.5%,差异有统计学意义(x2=5.137,P=0.023);携带XPG46C/C及C/T+T/T基因型的患者治疗有效率分别为47.6%、23.4%,二者间也有统计学差异(x2=5.729,P=0.017),联合分析显示A/A及C/C型化疗有效率最高,达63.0%,而A/A及C/T+T/T型最低,仅15.4%,四组间有显著统计学差异(x2=14.080,P=0.003)。2)89例患者中位TTP为7个月,XPA23A/A基因型中位TTP为11个月,A/G+G/G基因型为6个月,两者比较差异有显著性(x2=44.640,P<0.01);XPG46C/C基因型中位TTP为10个月,C/T+T/T基因型为6个月,两者也有统计学差异(x2=32.236,P<0.01)。联合分析显示,XPAA/A+XPGC/C型中位TTP最长,达到11个月,而A/G+G/G及C/T+T/T基因型最短,仅有4个月,四组间差异有显著统计学意义(x2=59.295,P<0.01)。结论:XPAA23G及XPGC46T单核苷酸多态性可单独及联合用于预测晚期NSCLC病人对铂类药物的化疗疗效及TTP,初步提示可以根据患者基因型来指导个体化治疗。     

XPA及XPG基因多态性与晚期非小细胞肺癌铂类药物化疗疗效及预后的关系

目的：研究DNA修复基因XPAA23G及XPGC46T位点基因多态性与晚期非小细胞肺癌铂类化疗疗效及预后的关系。方法：经病理学确诊的晚期非小细胞肺癌患者89例,化疗前提取其外周血DNA,用DNA测序技术检测XPA、XPG基因型,所有患者均接受2-4个周期铂类药物为基础的化疗。结果：1）89例患者中,携带XPA23A/A及A/G＋G/G基因型的化疗有效率分别为47.5%和24.5%,差异有统计学意义（x2=5.137,P=0.023）;携带XPG46C/C及C/T＋T/T基因型的患者治疗有效率分别为47.6%、23.4%,二者间也有统计学差异（x2=5.729,P=0.017）,联合分析显示A/A及C/C型化疗有效率最高,达63.0%,而A/A及C/T＋T/T型最低,仅15.4%,四组间有显著统计学差异（x2=14.080,P=0.003）。2）89例患者中位TTP为7个月,XPA23A/A基因型中位TTP为11个月,A/G＋G/G基因型为6个月,两者比较差异有显著性（x2=44.640,P〈0.01）;XPG46C/C基因型中位TTP为10个月,C/T＋T/T基因型为6个月,两者也有统计学差异（x2=32.236,P〈0.01）。联合分析显示,XPAA/A＋XPGC/C型中位TTP最长,达到11个月,而A/G＋G/G及C/T＋T/T基因型最短,仅有4个月,四组间差异有显著统计学意义（x2=59.295,P〈0.01）。结论：XPAA23G及XPGC46T单核苷酸多态性可单独及联合用于预测晚期NSCLC病人对铂类药物的化疗疗效及TTP,初步提示可以根据患者基因型来指导个体化治疗。     

白细胞介素一IB 基因多态性与胃癌发生的相关性研究

目的：探讨湖南衡阳地区白细胞介素-1B（IL-1B）基因多态性与胃癌的关系。方法：52例胃癌患者癌旁正常胃粘膜组织和55例慢性胃炎患者胃粘膜组织,应用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）分析技术,进行基因型检测,并对C／C、忻进行测序,比较各基因型在胃癌组和胃炎组中的分布差异。结果：IL-1B-31T、IL-1B-511T等位基因和IL-1B-31T/T、IL-1B-511T／T基因型在胃癌组的分布频率高于胃炎组（P〈0．05）,OR值分别为I．97（95％CI=1．15-3．59）、2．52（95％CI=1．45-4．39）和2．71（95％CI=1,10-6．66）、3,33（95％CI=1．14-9．73）。结论：在湖南衡阳地区IL-1B-3lT／T、IL-1B-511T/T基因型与胃癌发病风险相关。     

局部热疗联合替吉奥及奥沙利铂治疗胃癌腹腔转移的疗效观察

目的:评价局部热疗联合替吉奥及奥沙利铂治疗胃癌腹腔转移的疗效、患者生存质量及不良反应。方法:选择2011年1月-2016年1月来我院就诊的82例胃癌腹腔转移患者,随机分为观察组和对照组各41例。对照组采用替吉奥及奥沙利铂治疗,观察组在此基础上加用局部热疗,疗程为4周,治疗后对比两组患者的疗效、生存质量及不良反应情况。结果:治疗后,两组均有一定疗效,观察组的有效率为58.5%,明显高于对照组的31.7%,差异具有统计学意义(P0.05);观察组的生存质量提高率为73.2%,明显高于对照组的48.8%,差异具有统计学意义(P0.05);观察组发生呕吐13例,腹泻1例,口腔粘膜炎8例,对照组发生呕吐12例,3例腹泻,口腔粘膜炎9例,差异均无统计学意义(P0.05);观察组白细胞减少7例,对照组15例,差异有统计学意义(P0.05)。结论:局部热疗联合替吉奥及奥沙利铂治疗胃癌腹腔转移的疗效较好,患者生存质量改善,不良反应较轻。     

自噬通路基因多态性与晚期非小细胞肺癌含铂化疗疗效的相关性分析

对晚期非小细胞肺癌患者采用含铂化疗是肺癌临床治疗中非常重要的方法,然而不同患者对含铂化疗的敏感性却存在着明显的个体差异,这提示发现潜在的分子标志物对预测临床中含铂化疗疗效具有关键作用。本研究旨在探索自噬通路基因多态性与晚期非小细胞肺癌含铂化疗疗效之间的相关性,以期寻找可能影响含铂化疗药物敏感性的分子标记。本研究纳入了1004例接受含铂化疗的晚期非小细胞肺癌患者,分析了自噬通路中13个基因上的99个SNP位点与含铂化疗临床获益、无疾病进展时间及总生存时间之间的相关性。研究发现,位于ULK1基因的位点rs7953348(G>A) (P=0.017, OR:0.67, 95%CI:0.49~0.93)和rs12303764(A>C) (P=0.009, OR:0.63, 95%CI:0.45-0.89)及位于ATG14基因上的位点rs17742719(C>A) (P=0.002, OR:1.83, 95%CI:1.26~2.66)、rs8003279(A>G) (P=0.006, OR:1.65, 95%CI:1.16~2.35)和rs1009647(G>A) (P=0.002, OR:1.70, 95%CI:1.22~2.37)与临床获益存在显著关联,位于DRAM基因上的位点rs7955890(G>A) (P=0.004, HR:0.63; 95%CI:0.46~0.86)和rs17032060(G>A) (P=0.006, HR:0.65, 95%CI:0.48~0.88)及位于ATG3基因上的位点rs13082005(G>A) (P=0.012, HR:1.27,95%CI:1.05~1.53)与含铂化疗的无疾病进展时间显著相关,位于ULK1基因的位点rs7953348(G>A) (P=0.011, HR:0.74, 95%CI:0.58~0.93)和位于ATG10基因上的位点rs1864183(G>A) (P=0.016, HR:0.42, 95%CI:0.21~0.85)对含铂化疗的总生存时间有着显著影响。研究结果提示自噬通路在含铂化疗敏感性中发挥着重要作用,自噬通路基因多态性可能是预测含铂化疗疗效的潜在分子标志物,这可能为临床上肺癌的个体化医疗提供一定的理论基础。     

IL-17A基因单核苷酸位点多态性与胃癌预后的相关性研究

探讨白介素17A基因多态性与胃癌预后的关系。129例研究对象纳入生存分析,分成死亡和存活两组,用基因测序的方法检测血液样本IL-17A基因SNP位点rs3748067、rs17880588基因型分布。rs3748067位点有3种基因型T/T、C/T、C/C,rs17880588位点有2种基因型A/G、G/G。比较存活组和死亡组之间的基因型分布频率和单点等位基因分布频率,发现rs3748067的基因型C/T在死亡组的分布频率较存活组高,基因型T/T和C/C在死亡组的分布频率低于存活组,两组之间分布频率差异有统计学意义(P0.05)。杂合型C/T基因型在存活组分布低于死亡组(OR=2.051,CI=0.016~1.420),该位点基因型杂合可能为胃癌预后的一种危险因素。rs17880588的两种基因型A/G、G/G在存活组和死亡组的分布频率差异无统计学意义(P0.05)。结论:IL-17A基因rs3748067位点SNP与胃癌预后可能有相关性。     

奥沙利铂联合常规化疗治疗晚期结肠癌的临床观察

目的:研究奥沙利铂(L-OHP)联合化疗治疗晚期结肠癌的疗效.方法:选取60例晚期结肠癌患者,随机分为治疗组和对照组,每组各30例,对照组给予常规化疗治疗,治疗组给予L-OHP联合化疗治疗,观察比较两组的疗效和不良反应.结果:治疗组治疗总有效率(53.3％)显著高于对照组(36.7％)(P＜0.05);治疗组中初治患者治疗有效率(63.2％)显著高于复治患者(36.3％)(P＜0.05),也显著高于对照组中的初诊患者治疗有效率(38.9％)(P＜0.05).对照组中初治患者治疗有效率(38.9％)和复治患者(30.0％)相当(P＞0.05),复治患者的治疗有效率与对照组复治患者相当(P＞0.05).治疗组白细胞减少和神经毒性的发生率要高于对照组(P＜0.05),而治疗组出现口腔炎的比例低于对照组(P＜0.05),恶心呕吐、腹泻、血小板减少、手足综合征和肾毒性的发生率均相当(P＞0.05).结论:L-OHP联合化疗治疗晚期结肠癌初治患者具有较好的近期疗效和安全性,但其远期疗效和预后尚需进一步研究观察.     

奥沙利铂联合替吉奥胶囊治疗晚期大肠癌患者的临床疗效

目的:探讨奥沙利铂联合替吉奥胶囊治疗晚期大肠癌患者的临床疗效。方法:非盲法随机对照方法将患者分成试验组和对照组,各27例。试验组患者使用奥沙利铂联合替吉奥胶囊治疗,对照组患者使用奥沙利铂治疗,均为4个周期。评价两组治疗后的临床疗效和不良反应。结果:试验组:CR 1例,PR 11例,SD 10例,PD 5例。(CR+PR)RR 44.4%。中位疾病进展时间(TTP)9.5个月,中位生存期(MST)19.1个月。对照组:CR 0例,PR 5例,SD 8例,PD 15例。(CR+PR)RR 18.5%。中位疾病进展时间(TTP)8.6个月,中位生存期(MST)16.9个月。主要不良反应为血液毒性、胃肠道反应、外周神经炎及肝功能异常。试验组白细胞下降15例,对照组12例,试验组贫血发生为13例,对照组的为21例,试验组恶心、呕吐发生为18例,对照组为24例,试验组便秘发生为8例,对照组为15例,差异有统计学意义(P0.05)。结论:奥沙利铂联合替吉奥胶囊治疗晚期大肠癌患者相比单独使用奥沙利铂更加有效,更具优越性,不良反应更少,患者的生存质量得以改善,值得临床上推广应用。     

A genetic variant in the gene encoding the stress70 protein chaperone family member STCH is associated with gastric cancer in the Japanese population

Association analysis, based on linkage disequilibrium between specific alleles in the candidate loci and nearby genetic markers, has been proposed to identify genes conferring susceptibility to multifactorial diseases. Using the affected sib-pair method, we previously mapped four candidate chromosomal regions, 1p32, 2q33-q35, 11p13-p14, and 21q21, for gastric cancer by linkage analysis. To identify genes involved in the disease, we performed a gene-based association analysis of 66 genes, located on 21p11-21q22, using 126 single nucleotide polymorphisms (SNPs) as genetic markers in 373 patients with 250 controls. We found a significant association of five SNPs in the stress70 protein chaperon family member STCH gene with gastric cancer, especially with the non-cardia localization subgroup (P = 0.0005-0.02, odds ratio = 1.44-1.72). Comparisons of haplotype frequency showed significant association between TTGGC haplotype and gastric cancer (P = 0.0001, odds ratio = 1.59). These results suggest that, in the Japanese population, STCH might be a new candidate for conferring susceptibility to this disease.     

Ethnic differences in cytokine gene polymorphisms: potential implications for cancer development

Differences in incidence and outcome of cancer among ethnic groups may be explained by biological and/or socio-economic factors. Genetic variations that affect chronic inflammation, a potentially important risk factor for carcinogenesis, may differ across ethnic groups. Such differences may help explain cancer disparities among these groups. Single nucleotide polymorphisms (SNPs) within cytokine genes can affect cytokine levels and the degree of inflammation. Associations between cancer and some cytokine SNPs have been suggested. However, these have not been consistently replicated among populations, suggesting that SNP function may differ according to ethnicity, or that SNPs alone do not completely account for regulation of inflammation. We examined seven polymorphisms in African-American (n = 294) and Caucasian (n = 299) newborns in Louisiana: IL1B-511C > T, IL1B-31T > C, IL1B + 3954C > T, IL1RN*2, IL10-1082G > A, IL10-592C > A, and TNF-308G > A. African-American newborns had significantly higher frequencies of IL1B-511T, IL1B-31C, IL10-1082A and IL10-592A alleles and complete linkage equilibrium between IL1B + 3954 and IL1B-31. In contrast, IL1B + 3954T, IL1RN*2, and TNF-308A were more frequent in Caucasian newborns and exhibited strong linkage disequilibrium between IL1B + 3954 and IL1B-31. All allelic frequencies were significantly different between groups. We hypothesize that these dissimilarities may contribute to differences in the inflammatory response and cancer incidence and mortality between African-Americans and Caucasians in Louisiana.     

IL-8与胃癌关系的研究进展

IL-8是趋化性细胞因子,可以促进炎症细胞趋化和诱导细胞增殖,在胃癌组织中高表达。影响IL-8在胃癌组织中表达水平的因素包括幽门螺杆菌感染、NF-κB的干预、IL-8的基因多态性、表皮生长因子（EGF）的水平。IL-8主要参与胃癌的血管形成、促进金属蛋白酶的表达、影响E-cad和ICAM-1的水平、促进细胞有丝分裂、促使肿瘤转移等,对胃癌的发生、发展、预后均起重要的作用。选择性阻断IL-8及其受体具有抑癌作用,有望成为胃癌治疗的基础药物之一。     

Functional polymorphisms in the IL6 gene promoter and the risk of urinary bladder cancer in India

BackgroundInterleukin-6 is a multifunctional cytokine, which plays a key role in tumor proliferation and differentiation. Variations in its gene (IL6) sequence may affect the risk of developing various cancers, including urinary bladder cancer. The present study was done to find the association of functional polymorphisms in the IL6 promoter with urinary bladder cancer.Materials and methodsSingle nucleotide polymorphisms were genotyped in histologically confirmed 232 cases of urinary bladder cancer and 250 healthy controls. The controls subjects were matched to the cases by age, sex, and ethnicity. Genotyping of the polymorphisms (−174G>C; −572G>C, −596A>G) was undertaken by direct DNA sequencing. The level of association between the genotypes and urinary bladder cancer risk was estimated by odds ratios and 95% confidence intervals generated by applying the chi-square test. Linkage disequilibrium (LD) between SNPs and haplotype analysis were performed using Haploview software.ResultSignificantly higher number of smokers (p = 0.047), tobacco chewers (p = <0.001) and those with non-vegetarian food habits (p = 0.016) were seen in the case group. The distribution of genotypes at −174G>C locus differed significantly between cases and controls and the variant genotypes GC + CC were significantly rarer in the cases (p = 0.00073; OR = 0.52 95% CI 0.35–0.75). Variant genotypes (GC + CC) were more common in grade I than grade III tumors (p = 0.032), further suggesting a protective effect. No LD was found between the SNPs; however, the frequency of haplotype AGC was significantly lesser in the cases than controls (p = 0.0103), suggesting a protective effect. Genotype distribution at the other two loci (−572G>C and −596A>G) did not show association with bladder cancer.ConclusionsIL6 (−174G>C) substitution confers significant protection against the risk of urinary bladder cancer in the study population, while other substitutions in this gene (−572G>C and −596A>G) do not affect the risk. In general, there is a lack of studies on the cytokine gene polymorphisms in urinary bladder cancer.     

High frequency occurrence of 1-OPRD variant of PRNP gene in gastric cancer cell lines and Chinese population with gastric cancer

The prion protein gene PRNP encodes PrPc and PrPsc, causing a number of neurological disorders. Approximately 10-15% of human prion disease is inherited and more than 20 pathogenic mutations have been found. Most of the genetic alterations are point mutations, with the exception of genetic insertions of one to nine extra octapeptide repeats occurring in the important octapeptide-coding region. Our previous work showed that PrPc was overexpressed in gastric cancer. We wondered whether mutations of PrPc existed in human gastric cancer. DNA sequencing and gel electrophoresis were used to determine the possible mutation of PrPc in patients and cell lines of gastric cancer. We found that 1-OPRD (one octapeptide-repeat deletion) homozygosity or heterozygosity exists in several gastric cancer cell lines, e.g. MKN28 and KatoIII are homozygous for 1-OPRD, and SGC7901 and BGC-823 are heterozygous for 1-OPRD. The mutation frequency in tissues of gastric cancer cases is significantly higher than that in the common population (p<0.05). All positive cases in gastric cancer were found to be heterozygous for 1-OPRD. Further study of the variant may be helpful in understanding the mechanisms of occurrence and development of clinical gastric carcinoma as well as the biology of the mysterious gene PRNP.     

单核苷酸多态性SNP（rs34040607）与中国人胃癌相关性的研究

目的：探讨胃癌组织中17号染色体q25-3区单核甘酸多态性位点rs34040607与人胃癌的相关性。并初步探索其可能的生物学机制和效应。方法：应用Taqman探针实时定量PCR分型法,检测50例胃癌患者及对照非胃癌患者基因组中此位点的多态性。应用RT．PCR法,检测胃癌组织中此位点转录产物及转录方向。应用最小自由能方法预测此位点突变对非编码RNA发夹结构形成的影响。结果：中国人胃癌患者中此位点多态性存在高变异。与正常对照人群存在显著差异。该位点存在转录活性,且转录方向为单向,由着丝粒向端粒方向转录。该点突变导致转录的非编码RNA发夹结构改变。结论：SNP位点rs34040607变异可以作为胃癌易感性预测的靶点,在未来的基因筛查中可作为一个重要候选位点,对该位点的转录及对RNA发夹结构的改变揭示了其发挥功能的一个可能的机制。     

Rapid genotyping of three polymorphisms in the LBP gene using a triplex pyrosequencing approach

We described a triplex polymerase chain reaction (PCR) and triplex pyrosequencing assay which allowed a simultaneous determination of three tag single nuleotide polymorphisms (tag SNPs) in the lipopolysaccharide-binding protein (LBP) gene: rs1780623, rs11536972 and rs2232618. This method enables a fast and cost-effective genotyping and a simultaneous determination of the three tag SNPs.