川东北地区人群结直肠癌患者UGT1A1*28基因多态性与伊立替康所致毒副反应的相关性

目的:观察结直肠癌患者UGT1A1*28基因多态性的分布频率,了解UGT1A1*28基因多态性与结直肠癌患者应用伊立替康联合5-氟尿嘧啶化疗毒副反应的相关性。方法:从384例接受伊立替康联合氟尿嘧啶一线化疗的晚期结直肠癌病例中采外周血提取DNA。采用PCR 法扩增目的基因片段,直接测序法分析UGT1A1*28基因多态性。临床观察并评价患者化疗毒副反应分级,统计分析UGT1A1*28基因表型与化疗毒副反应相关性。结果:全部 384例患者 UGT1A1*28基因多态性分布情况:TA6/6野生基因型287例(74.7％),TA6/7杂合基因型73例（19.0％）,TA7/7纯合基因型24例（6.3％）。化疗毒副反应和UGT1A1*28基因多态性进行临床单因素分析显示UGT1A1*28基因纯合型TA7/7、杂合型TA6/7与3-4度白细胞减少、中性粒细胞减少、腹泻、胆红素升高具有明显相关性（P<0.01）,UGT1A1*28基因纯合型TA7/7及杂合型TA6/7患者发生中性粒细胞减少的风险较UGT1A1*28基因野生型TA6/6患者高5.625倍（OR=5.625）。UGT1A1*28基因纯合型TA7/7和UGT1A1*28基因杂合型TA6/7患者发生腹泻的风险较UGT1A1*28基因野生型TA6/6患者高6.778倍（OR=6.778）。结论:UGT1A1*28基因纯合型TA7/7及杂合型TA6/7患者应用伊立替康化疗后发生重度中性粒细胞减少、重度腹泻的风险高于UGT1A1*28基因野生型TA6/6,为临床伊立替康用药选择、剂量调整、毒副反应的提前干预提供理论依据。     

UGT1A1基因多态性在FOLFIRI方案二线治疗转移性结直肠癌中的临床意义

目的 探讨尿苷二磷酸葡萄糖醛酸转移酶（UGT）1A1基因多态性在FOLFIRI方案二线治疗转移性结直肠癌（mCRC）中的安全性和作为疗效预测指标的价值。方法在FOLFIRI方案化疗前分离mCRC患者外周血中单核细胞,采用荧光定量PCR-HRM法测定UGT1A1基因型。根据NCI CTC 3.0和RECIST 10标准分别评价化疗的不良反应和疗效,并分析UGT1A1基因多态性与不良反应和近期有效率（RR）的关系。用Kaplan-Meier法进行生存分析,Log-rank 检验分析UGT1A1基因型对无进展生存期（PFS）的影响。结果38例患者中,UGT1A1*28位点的野生型（TA6／6）有31例（81.6％）,杂合突变型（TA6／7）2例（5.3％）,纯合突变型（TA7／7）5例（13.2％）;UGT1A1*6位点的野生型（G／G）有28例（73.7％）,杂合突变型（G／A）8例（21.1％）,纯合突变型（A／A）2例（5.3％）。在3～4级延迟性腹泻和中性粒细胞减少的发生率方面,UGT1A1*28的野生型（TA6／6）显著低于TA6／7和TA7／7基因型（P＜0.05）,UGT1A1*6的野生型（G／G）也显著低于G／A和A／A基因型（P＜0.05）。RR和PFS在UGT1A1各种基因型之间差异无统计学意义（P＞0.05）。结论 在FOLFIRI方案二线治疗mCRC中,UGT1A1*28位点和UGT1A1*6位点突变可以作为严重的延迟性腹泻和中性粒细胞减少的预测指标,但UGT1A1基因多态性与疗效无关。     

UGT1A1基因多态性与伊立替康安全性和有效性的临床研究

  目的  观察57例应用伊立替康治疗进展期消化道肿瘤患者的安全性和有效性。  方法  采用全血基因组DNA提取、PCR法扩增目的基因片段, 直接测序法分析UGT1A1基因多态性, 检测2011年8月至2012年6月在河北医科大学第四医院肿瘤内科住院治疗的57例进展期消化道肿瘤患者应用伊立替康的情况, 观察并记录化疗中出现的不良反应以及疗效。  结果  57例进展期消化道肿瘤患者中, UGT1A1基因启动子区28位点, TA序列6次重复的纯合野生型TA6/6有43例（75.4%）; 基因型为TA序列6次和7次重复的杂合型TA6/7有13例（22.8%）; 基因型为TA序列7次重复的纯合突变型TA7/7有1例（1.8%）。UGT1A1基因启动子区6位点野生型G/G有48例（84.2%）, 杂合突变型G/A有7例（12.3%）, 纯合突变型A/A有2例（3.5%）。在57例采用含伊立替康方案化疗的进展期消化道肿瘤患者中, UGT1A1基因启动子区28位点, TA6/6、TA6/7和TA7/7野生型和突变型发生3级以上中性粒细胞减少者分别为7.0%、14.3%, 发生3级以上腹泻者分别为9.3%、14.3%, 其中纯合突变型仅1例患者, 100%的发生率。UGT1A1基因启动子区6位点, G/G、G/A和A/A野生型和突变型发生3级以上中性粒细胞减少者分别为4.2%、55.6%, 发生3级以上腹泻者分别为12.5%、44.4%, 具有统计学差异。各组之间疗效无统计学差异。  结论  患者UGT1A1*28和UGT1A1*6多态性分布基本一致, UGT1A1*6突变型患者应用伊立替康化疗发生3级以上中性粒细胞减少和腹泻的风险增加, 而UGT1A1*28突变型与以上不良反应并无绝对相关性, UGT1A1各基因型之间疗效无明显差异。能否通过对UGT1A1的筛查, 选择合适患者安全有效的应用伊立替康, 值得临床进一步扩大样本量深入研究。      

UGT1A1基因多态性与伊立替康临床用药安全性及疗效的关系

目的：研究 UGT1A1基因多态性与伊立替康治疗结直肠癌患者的不良反应及疗效之间的关系。方法：自外周血中抽提基因组 DNA,进行 PCR 扩增,应用直接测序法分析2012年3月至2013年3月,于我院行基因检测的65例结直肠癌患者 UGT1A1*28和 UGT1A1*6基因多态性的分布情况。并对这65例应用含伊立替康方案化疗的患者出现的不良反应及化疗疗效,进行观察记录,比较不同基因型间的差异。结果：65例患者中,UGT1A1*28野生型 TA6／6有49例（75．4％）,杂合突变型 TA6／7有14例（21．5％）,纯合突变型TA7／7有2例（3．1％）。UGT1A1*6野生型 G／G 有47例（72．3％）,杂合突变型 G／A 有15例（23．1％）,纯合突变型 A ／A 有3例（4．6％）。在以上65例结直肠癌患者中,UGT1A1基因启动子区28位点,TA6／6、TA6／7和TA7／7型,发生3级以上腹泻者分别为8．2％、37．5％;发生3级以上中性粒细胞减少者分别为28．6％、62．5％。UGT1A1基因启动子区6位点,G／G、G／A 和 A ／A 型,发生3级以上腹泻者分别为12．8％、44．4％;发生3级以上中性粒细胞减少者分别为14．9％、22．2％。各组之间疗效无统计学差异。结论：患者 UGT1A1*28和UGT1A1*6多态性分布基本一致,UGT1A1*28突变型可以使应用含伊立替康化疗患者发生3级以上腹泻和中性粒细胞减少的风险增加。UGT1A1*6突变型可增加3级以上腹泻的发生风险。因此,UGT1A1基因型的检测对伊立替康相关的不良反应有一定的预测作用,可提高用药安全性,在临床用药中起到了指导作用。     

UGT1A1基因多态性与伊立替康为主方案治疗晚期结直肠癌的毒性和疗效的相关性分析

目的 探讨中国汉族人结直肠癌患者尿苷二磷酸葡糖苷酸转移酶1A1（UGT1A1）基因多态性分布,评价UGT1A1基因多态性与伊立替康（CPT-11）为主方案治疗晚期结直肠癌的毒性和疗效的关系。方法 以CPT-11为主的FOLFIRI方案（CPT-11 180mg／m²）和IFL方案（CPT-11 125mg／m²）治疗晚期结直肠癌,检测患者的UGT1A1*28和UGT1A1*6基因型,分析UGT1A1基因多态性及其与化疗毒性、疗效和预后的相关性。结果 共纳入192例患者,189例行UGT1A1*28和UGT1A1*6基因型检测,野生型占37.6％,1个位点变异型占43.9％,2个位点突变异型占18.5％。183例可评价毒副反应,3～4级中性粒细胞减少的发生率为26.6％（51／183）;3～4级迟发性腹泻的发生率为15.1％（29／183）。2个位点变异的患者3～4级迟发性腹泻发生率显著高于野生型患者（26.5％vs.9.0％,P=0.021）。UGT1A1*28野生型、杂合突变型、纯合突变型的2～4级迟发性腹泻的发生率分别为29.6％、37.5％和88.9％,差异具有统计学意义（P=0.02）。UGT1A1*28纯合突变者4级中性粒细胞减少的发生率为33.3％,高于UGT1A1*28野生型的9.6％,但差异无统计学意义（P=0.07）。Logistic多因素分析显示UGT1A1*28和UGT1A1*6基因型是2～4级迟发性腹泻的影响因素。CPT-11剂量高者的3～4级中性粒细胞减少（OR=5.666,95%CI：2.088～15.377,P=0.001）和2～4级迟发性腹泻（OR=4.481,95%CI：1.568～12.807,P=0.005）发生率也显著升高。158例可评价疗效,获CR 3例、PR 30例、SD 91例、PD 34例,总有效率为20.9％。2个位点变异患者的有效率为33.3％,高于野生型的15.3％,但差异无统计学意义（P=0.063）。治疗时间在6周以下者疾病进展的风险显著增加（OR=6.106,95％CI：1.680～22.197,P=0.006）。Cox多因素分析显示,ECOG评分、治疗时间及治疗方案是影响患者预后的独立因素,而UGT1A1基因多态性与预后无关。结论 UGT1A1*28和UGT1A1*6基因型2个位点变异的患者应用CPT.11为主方案化疗的不良反应发生率较高,但疗效较好,由不良反应导致的治疗时间缩短可能会影响其获得更好的疗效。     

尿苷二磷酸葡萄糖醛酸转移酶1A1~*6和尿苷二磷酸葡萄糖醛酸转移酶~*28基因多态性与伊立替康疗效及不良反应的关系

目的观察尿苷二磷酸葡萄糖醛酸转移酶1A1(UGT1A1*)6和UGT1A1*28基因多态性与伊立替康化疗疗效及不良反应之间的关系。方法采用外周静脉血DNA抽提、聚合酶链反应(PCR)扩增和焦磷酸测序方法分析UGT1A1*6和UGT1A1*8基因型,收集72例2010年1月至2013年12月间接受伊立替康治疗的晚期恶性肿瘤患者的临床资料,观察患者用药期间的药物不良反应及化疗疗效,分析基因多态性与化疗不良反应及近期疗效的关系。结果 72例恶性肿瘤(结直肠癌、小细胞肺癌)患者中,UGT1A1*6野生型G/G 40例(55.6%),杂合突变型G/A 21例(29.2%),纯合突变型A/A 11例(15.2%);UGT1A1*28野生型(TA)6/(TA)651例(70.8%),杂合突变型(TA)6/(TA)720例(27.8%),纯合突变型(TA)7/(TA)71例(1.4%)。UGT1A1*6突变型患者(G/A和A/A)3~4级腹泻和3~4级中性粒细胞减少的发生率分别为65.6%和43.7%,野生型(G/G)分别为30.0%和17.5%,差异均有统计学意义(均P<0.05)。UGT1A1*28突变型患者[(TA)6/(TA)7和(TA)7/(TA)7]3~4级腹泻的发生率(42.9%)高于野生型(17.6%,P<0.05)。各组之间近期化疗疗效差异无统计学意义(P>0.05)。结论 UGT1A1*6突变型患者应用伊立替康化疗发生3级及以上中性粒细胞减少及迟发性腹泻的风险增加,而UGT1A1*28突变型患者发生3级以上迟发性腹泻的风险增加,UGT1A1各基因型之间疗效无明显差异,通过检测UGT1A1基因多态性能够合理选择应用伊立替康。     

UGT1A1*28基因多态性与伊立替康疗效和毒副作用相关性研究进展

目的:总结UGT1A1*28基因多态性与伊立替康(CPT-11)疗效及毒性的相关性。方法:应用PubMed及CNKI期刊全文数据库检索系统,以"UGT1A1*28基因多态性、CPT-11、疗效和毒性"为关键词,检索2000-01-2012-05相关文献,共检索到英文文献208篇和中文文献8篇。纳入标准:1)CPT-11的体内代谢;2)UGT1A1*28基因型特点;3)一线化疗;4)UGT1A1*28基因多态性与疗效和毒性的关系。根据纳入标准符合分析的文献28篇。结果:CPT-11的体内代谢与尿苷二磷酸葡萄糖醛酸转移酶家族(UGTS)密切相关,UGTS的表达由UGT1A1基因位点决定。UGT1A1*28为7个TA重复序列,包括纯合型(TA7/TA7)和杂合型(TA6/TA7),随着TA重复序列数目的增加,CPT-11相关毒性增加。多数研究表明,UGT1A1*28基因多态性与CPT-11化疗疗效无关。在欧美人群中,UGT1A1*28与CPT-11的剂量限制性毒性,即延迟性腹泻和中性粒细胞减少有明显相关性;在亚洲人群中,UGT1A1*28与腹泻的关系更为密切。结论:UGT1A1*28基因多态性具有种族差异,今后尚需开展大规模的前瞻性研究来验证UGT1A1*28基因多态性与CPT-11疗效和毒性的关系,从而指导个体化治疗。     

UGT1A1*28基因多态性与FOLFIRI方案化疗致迟发性腹泻的关系

目的 探讨尿苷二磷酸葡糖苷酸转移酶1A1 (UGT1A1)基因多态性与FOLFIRI方案化疗致迟发性腹泻的关系.方法 选取晚期消化道肿瘤患者201例,在FOLFIRI方案化疗前抽取外周血进行UGT1A1* 28基因检测,观察并记录出现迟发性腹泻的情况.分析基因多态性与化疗致3级以上迟发性腹泻的关系.结果 201例晚期消化道肿瘤患者中UGT1A1*28纯合野生型TA6/6占77.11％(155/201),突变型TA6/7和TA7/7共占22.89％(46/201),野生型和突变型1、2级腹泻发生率分别为45.16％ (70/155)和39.13％ (18/46),3、4级腹泻发生率分别为9.68％(15/155)和19.57％(9/46).基因突变型患者3、4级迟发性腹泻的发生率与野生型患者相比差异无统计学意义(x2=3.318,P=0.190).结论 在采用FOLFIRI方案化疗的晚期消化道肿瘤患者中,UGT1A1 * 28基因突变型并未增加患者发生3级以上迟发性腹泻的风险.     

UGT1A1*28基因多态性与晚期结直肠癌伊立替康化疗疗效及不良反应的关系

目的:尿苷二磷酸葡糖醛酸转移酶1A1(uridine-diphosphoglucuronosyl transferase 1A1, UGT1A1)作为伊立替康重要的药物代谢酶,其基因多态性可显著影响该酶的活性.本研究旨在观察UGT1A1*28基因多态性与晚期结直肠癌伊立替康化疗疗效和不良反应之间的关系.方法:回顾性研究64例接受伊立替康/氟尿嘧啶一线化疗的晚期结直肠癌患者.从患者外周血白细胞中提取DNA,应用直接测序法检测UGT1A1*28 TATA盒基因序列,并分析基因多态性与化疗不良反应和近期疗效的关系.结果: 51例(79.7%)患者的UGT1A1*28基因启动子区TA序列重复6次,为纯合野生型(TA)6/(TA)6;10例(15.6%)患者的基因型为TA序列重复6次和7次的杂合型(TA)6/(TA)7;3例(4.7%)患者的TA序列重复7次,为纯合突变型(TA)7/(TA)7.UGT1A1*28非野生型的基因多态性可增加患者发生Ⅲ度以上腹泻的风险(38.5% vs 9.8%,P=0.035);UGT1A1*28非野生型基因患者接受伊利替康化疗时,需要下调剂量的比率明显高于野生型基因者(46.2% vs 15.7%,P=0.046).64例患者中28例(43.8%)化疗有效,其中UGT1A1*28野生型基因者22例,非野生型基因者6例,2组的反应率差异无统计学意义(46.2% vs 43.1%,P=0.845).结论:在应用伊立替康化疗的患者中,UGT1A1*28基因启动子区TATA盒基因多态性(TA)6/(TA)7或(TA)7/(TA)7基因型可增加晚期结直肠癌患者接受伊立替康化疗后,发生Ⅲ度以上腹泻的风险,但不影响化疗的近期疗效.     

伊立替康联合顺铂或5-FU治疗UGT1A1*28野生型TA6/6患者不良反应的比较

目的：比较尿苷二磷酸葡萄糖醛酸转移酶1A1（UGT1A1）*28启动子为野生型的TA6/6患者在使用伊立替康（irinotecan,CPT-11）联合顺铂与CPT-11联合5-FU/亚叶酸钙治疗时不良反应方面的差异。方法根据采取的治疗方案将98例UGT1A1*28野生型TA6/6患者分为CPT-11联合顺铂组（IP组,n＝47）和CPT-11联合5-FU/亚叶酸钙组（FOLFIRI组,n＝51）,对患者进行UGT1A1*28启动子多态性检测,比较不良反应差异。结果在总体3～4级不良反应方面,IP组的发生率（61.7%）明显高于FOLFIRI组（39.2%）,且组间差异具有统计学意义（P=0.026）。在血液学不良反应方面,IP组3～4级白细胞减少、中性粒细胞减少、血小板减少和血红蛋白减少发生率分别为34.0%、51.1%、14.9%和8.5%,FOLFIRI组的发生率分别为11.8%、29.4%、2.0%、0,组间差异均有统计学意义（均P＜0.05）;在非血液学方面,FOLFIRI组3～4级迟发性腹泻发生率为9.8%,IP组未发生3～4级腹泻,两组间发生率的差异有统计学意义（P=0.028）。结论 UGT1A1*28野生型TA6/6患者在接受CPT-11联合顺铂和CPT-11联合5-FU/亚叶酸钙两种化疗方案治疗的不良反应谱存在差异;应用CPT-11时,不但要考虑到UGT1A1*28启动子多态性对不良反应的影响,而且还要考虑CPT-11联合不同药物出现不良反应情况。     

Reaction of 1-n-propyl-1-nitrosourea with DNA in vitro

[n-propyl-2,3-³H]1-n-Propyl-1-nitrosourea (PNU) (sp. act.: 665mCi/mmol) was synthesized and incubated with calf thy-mus DNAat pH 7.0 and 37°C in vitro. The degree of alkylation wasproportional to the concentration of PNU added. The extent was68 pmol/mg of DNA at 1 mM PNU. After mild add hydrolysis, purinebases were separated by Sephadex G-10 column chromatography.Although O⁶-n-propylguanine and O⁶-iso-propylguanine were separatedby this method, 7-n-propylguanine and 7-iso-propylguanine werenot separated. Then we used a h.p.l.c. equipped with a µBonda-pak-C₁₈reverse phase column with a linear gradient elution. 7-n-Propylguanineand O⁶-n-propylguanine were identified as major reaction products,and 7-iso-opropylguanine and O⁶-iso-propylguanine were identifiedas minor reaction products. The ratio of O⁶-n- and iso-propylguanine/7-n-and iso-propylguanines was 0.73. This ratio is similar to thatproduced by 1-ethyl-1-nitrosourea and 1-n-butyl-1-nitrosourea.     

Subtype Analysis of HTLV-1 in Patients with HTLV-1 Uveitis

The hypothesis that HTLV-1 uveitis, a recently identified disease entity associated with human T-cell leukemia virus type I (HTLV-1), is caused by a specific subtype of the virus was tested. The nucleotide sequences of the long terminal repeat of HTLV-1 from five patients with HTLV-1 uveitis (HU) and four with adult T-cell leukemia were phylogenetically analyzed. Our results showed that both subtypes which had been identified in Japan were associated with HU, indicating that there was no difference in pathogenicity between these phylogenetic subtypes. One of the subtypes was more frequently isolated in Okinawa than in Kyushu, suggesting a bias in the prevalence of each subtype among the inhabitants of these two areas of Japan.     

Hypermethylation of HPP1 is associated with hMLH1 hypermethylation in gastric adenocarcinomas

The HPP1 gene was initially discovered because of its frequent hypermethylation in hyperplastic colon polyps, but it is also hypermethylated in colorectal adenomas and carcinomas. Expression of the DNA mismatch repair gene hMLH1 is diminished or absent in some hyperplastic polyps, and it has been suggested that HPP1 inactivation is associated with the progression of microsatellite-unstable colorectal tumors. We sought then to determine the prevalence of HPP1 silencing by DNA methylation in gastric adenocarcinomas and to define any association of this event with microsatellite instability (MSI) or hMLH1 hypermethylation. Thirty-two matched normal-gastric adenocarcinoma DNA pairs were studied for MSI status and hypermethylation of HPP1 and hMLH1. Five (100%) of 5 MSI-H tumors, 2 (50%) of 4 MSI-L tumors, and 8 (35%) of 23 MSS tumors demonstrated HPP1 hypermethylation. Eight (25%) of 32 tumors (5 of 5 MSI-H, 2 of 4 MSI-L, and 1 of 23 MSS) showed evidence of hMLH1 hypermethylation. All (8 of 8) of these hMLHI-methylated tumors demonstrated concomitant methylation at the HPP1 locus: there were no cases of hMLH1 methylation occurring in the absence of HPP1 methylation. In gastric adenocarcinoma, hypermethylation frequently targets HPP1. Moreover, hMLH1 hypermethylation occurs predominantly in the setting of HPP1 hypermethylation. HPP1 hypermethylation may represent an early event in mismatch repair-deficient gastric tumorigenesis.     

Association of WT1 IgG antibody against WT1 peptide with prolonged survival in glioblastoma multiforme patients vaccinated with WT1 peptide

We previously evaluated Wilms’ tumor gene 1 (WT1) peptide vaccination in a large number of patients with leukemia or solid tumors and have reported that HLA‐A*24:02 restricted, 9‐mer WT1‐235 peptide (CYTWNQMNL) vaccine induces cellular immune responses and elicits WT1‐235‐specific cytotoxic T lymphocytes (CTLs). However, whether this vaccine induces humoral immune responses to produce WT1 antibody remains unknown. Thus, we measured IgG antibody levels against the WT1‐235 peptide (WT1‐235 IgG antibody) in patients with glioblastoma multiforme (GBM) receiving the WT1 peptide vaccine. The WT1‐235 IgG antibody, which was undetectable before vaccination, became detectable in 30 (50.8%) of a total of 59 patients during 3 months of WT1 peptide vaccination. The dominant WT1‐235 IgG antibody subclass was Th1‐type, IgG₁ and IgG₃. WT1‐235 IgG antibody production was significantly and positively correlated with both progression‐free survival (PFS) and overall survival (OS). Importantly, the combination of WT1‐235 IgG antibody production and positive delayed type‐hypersensitivity (DTH) to the WT1‐235 peptide was a better prognostic marker for long‐term OS than either parameter alone. These results suggested that WT1‐235 peptide vaccination induces not only WT1‐235‐specific CTLs as previously described but also WT1‐235‐specific humoral immune responses associated with antitumor cellular immune response. Our results indicate that the WT1 IgG antibody against the WT1 peptide may be a useful predictive marker, with better predictive performance in combination with DTH to WT1 peptide, and provide a new insight into the antitumor immune response induction in WT1 peptide vaccine‐treated patients.     

Early-Onset Breast Cancer in a Family with Neurofibromatosis Type 1 Associated with a Germline Mutation in BRCA1

Neurofibromatosis type 1 (NF1), which may occur as an autosom-al dominant disorder, is caused by the absence of neurofibromin protein due to somatic mutations in the NF1 gene, and it has been associated with an increased risk of breast cancer. Herein we describe a family with two women affected by both NF1 and early-onset breast cancer. We evaluated whether the concomitance of NF1 and early-onset breast cancer could be due to disease-causing mutations in both NF1 and BRCA1 gene in a Korean family with clinical features of both NF1 and hereditary breast cancer. Mutation analyses identified nonsense mutations in NF1 and BRCA1 genes. Our findings indicate that an awareness of the possible concomitance of NF1 and BRCA1 gene mutations is important for identifying the genetic origin of early-onset breast cancer in patients with NF1 to achieve early detection of cancers and decrease breast cancer-associated morbidity and mortality in these patients.     

ERCC1和Pim-1表达与非小细胞肺癌化疗疗效的相关性

目的:探讨非小细胞肺癌(non-small cell lung cancer,NSCLC)患者肺癌组织标本中ERCC1和Pim-1的表达与临床特征及化疗疗效的相关性。方法:对我院病理确诊的70例NSCLC患者肿瘤组织,通过实时定量荧光PCR法检测ERCC1和Pim-1基因mRNA表达水平,回顾性分析ERCC1和Pim-1基因表达与临床病理关系、铂类化疗疗效和总生存情况。结果:70例NSCLC患者肿瘤组织中ERCC1和Pim-1高表达患者比率分别为37.14%（26/70）和61.43%（43/70）,ERCC1高表达与性别、吸烟史、组织类型、TNM 分期均无关（P＞0.05）,Pim-1高表达与性别、吸烟史相关（P＜0.05）,而与组织类型、TNM分期无关（P＞0.05）。ERCC1和Pim-1共同高表达率为20.00%（14/70）。ERCC1高表达组患者化疗有效率（19.23%,5/26）显著低于低表达组患者（47.73%,21/44）(P＜0.05)。Pim-1高表达组患者化疗有效率（34.88%,15/43）和低表达组患者（40.74%, 11/27）无统计学差异(P＞0.05)。ERCC1和 Pim-1高表达组的中位生存期（median survival time,MST）为27个月和24个月低于低表达组的33个月和 27个月,但无统计学差异（P＞0.05）。结论:NSCLC患者中ERCC1低表达组患者化疗有效率和存活率高,是化疗受益的指标。     

Identification of MEN1 gene mutations in families with MEN 1 and related disorders

Following identification of the MEN1 gene, we analysed patients from 12 MEN 1 families, 8 sporadic cases of MEN 1, and 13 patients with MEN 1-like symptoms (e.g. cases of familial isolated hyperparathyroidism (FIHPT), familial acromegaly, or atypical MEN 1 cases) for the presence of germline MEN1 mutations. The entire coding region of the MEN1 gene was sequenced, and mutations were detected in 11 MEN 1 families; one sporadic MEN 1 patient, one case of FIHPT and one MEN 1-like case. Constitutional DNA samples from individuals without MEN1 mutations were digested with several restriction enzymes, Southern blotted and probed with MEN1 cDNA to analyse for the presence of larger deletions of the MEN1 gene unable to be detected by PCR. One MEN 1 patient was found to carry such a deletion. This patient was heterozygous for the D418D polymorphism, however sequence analysis of RT-PCR products showed that only the variant allele was transcribed, thus confirming the result obtained by Southern analysis, which indicated loss of a region containing the initiation codon of one allele.     

Association of CYP1A1 polymorphisms with breast cancer in North Indian women

Cytochrome P-450 (CYP) 1A1 is a candidate gene for low penetrance breast cancer (BC) susceptibility. Evidences demonstrate that ethnic differences in BC incidence may be partly due to genetic factors, including polymorphisms in the genes. In the present case control study four CYP1A1 gene polymorphisms, m1 (T6235C), m2 (A4889G), m3 (T5639C), and m4 (C4887A) were studied for their association with BC conjointly with the known risk factors such as age, menopausal status, diet, and life style. Polymorphisms of CYP1A1 gene were detected by PCR-RFLP method. The homozygous mutant (G/G) of m2 polymorphism was significantly associated with BC. Consequently, association of both m2 heterozygous mutant genotype (A/G) and combined group [homozygous (G/G) plus heterozygous (A/G) mutant genotype] showed association with postmenopausal women. Incidences of BC were also found to be independent of clinicopathological factors except heterozygous mutant genotype (A/G) m2 showed association with dietary factors and high grade tumors while homozygous mutant (G/G) m2 showed association with ER/PR-positive BC cases. Wild-type m3 was observed in all the subjects in cases as well as in controls. No significant association was observed between m1 and m3 polymorphisms and BC risk in all the subjects as well as when stratified into pre- and postmenopausal subjects. This indicates that out of ml and m2 polymorphisms that have been reported in Asians, only m2 is associated with North Indians.