错配修复基因MLH1、MLH2、MHL6、PMS2在胃癌组织中的表达及与上皮间质转换相关性

目的 分析错配修复基因(MMR) MLH1、MSH2、MSH6和PMS2在胃癌组织中表达及与上皮间质转换的相关性。方法 收集2019年12月至2020年6月期间承德市中心医院病理科胃癌活检及手术标本127例，采用免疫组化技术检测MLH1、MSH2、MSH6和PMS2表达情况，计算MMR蛋白表达缺失率，分析其与临床病理特征及上皮间质转换标志物水平相关性，比较MMR蛋白表达缺失患者与MMR蛋白表达非缺失组患者生存周期。结果 127例胃癌组中MMR蛋白缺失率为31.5%(40/127),MLH1、MSH2、MSH6、PMS2表达缺失率分别为20.47%(26/127)、14.17%(18/127)、8.66%(11/127)、16.54%(21/127);MMR蛋白缺失率与淋巴结转移、肿瘤分化程度、TNM分期有关(P<0.05);MMR蛋白表达与上皮标志物E-cadherin呈正相关(r=0.524,P<0.05),MMR蛋白表达与间质标志物Vimentin呈负相关(r=-0.471,P<0.05),与MMR蛋白表达缺失组比较，MMR蛋白表达非缺失组生存时间显著延长。结论 ...     

MMR状态和肿瘤出芽在胃腺癌中的临床意义

目的 在胃腺癌中检测错配修复蛋白(mismatch repair, MMR)表达状态和肿瘤出芽(tumor budding, TB)分级情况,并分析其与胃腺癌患者的临床病理参数及预后的相关性。方法 运用免疫组织化学方法检测171例胃腺癌患者的错配修复蛋白MLH1、PMS2、MSH2、MSH6的表达状态,并在HE切片中对TB分级进行评估,分析MMR表达及TB与临床病理参数及预后的关系。结果 171例胃腺癌中,22例(12.9%)为错配修复蛋白缺陷(deficiency of MMR,dMMR),以MLH1和PMS2蛋白联合缺失(13/22,59.1%)为主,其余6例(27.3%)为MSH2和MSH6蛋白联合缺失,3例(13.6%)为MLH1蛋白单独缺失。dMMR型胃腺癌患者与错配修复完整(mismatch repair proficiency, pMMR)组相比,在性别、年龄、Lauren分型、肿瘤最大径、淋巴结有无转移、TB分级等临床病理特征方面存在显著差异,而在分化程度、TNM分期、肿瘤位置、肿瘤浸润深度、有无远处转移、有无脉管癌栓、是否神经侵犯方面均无明显差异。TB分级与患者的病理...     

子宫内膜癌组织中DNA错配修复基因表达及意义

目的探讨DNA错配修复基因（MMR）在子宫内膜癌发生、发展中的作用。方法研究对象为80例子宫内膜癌组织[内膜癌组,其中可疑Lynch综合征相关子宫内膜癌（以下简称Lynch内膜癌）18例],12例子宫内膜非典型增生组织（增生组）,20例正常周期子宫内膜组织（正常组）。采用免疫组织化学AP法检测各组MMR蛋白h MLH1、h MSH2、h MSH6及h PMS2表达,其中≥1项表达阴性即判为MMR蛋白缺失。分析MMR蛋白缺失与内膜癌肿瘤分期、分级的关系;不同年龄内膜癌及可疑Lynch内膜癌者MMR缺失情况。结果增生组、内膜癌组及正常组MMR蛋白缺失率分别为33.33%（4/12）、36.25%（29/80）、0,增生组与内膜癌组比较无显著差异,但二者均明显高于正常组,P〈0.05。内膜癌组≤45岁者MMR缺失率明显高于年龄≥60岁者;18例可疑Lynch内膜癌患者MMR缺失率（88.89%）明显高于另外62例子宫内膜癌患者MMR蛋白缺失率（17.74%）,P〈0.05。结论 MMR蛋白表达缺失可促进子宫内膜癌（尤其是低龄子宫内膜癌）及子宫内膜非典型增生的发生及发展。     

错配修复蛋白和Ki-67在结直肠癌中的表达及其临床意义

背景:结直肠癌(CRC)是常见的癌症之一,是具有多种生物学发病机制的异质性疾病实体。目的:探讨错配修复蛋白(MMRP)和Ki-67蛋白在CRC中的表达,分析微卫星不稳定性(MSI)、Ki-67与CRC临床病理特征的关系。方法:回顾性分析2014年1月—2016年12月苏州大学附属第一医院收治的90例CRC患者的临床病理资料,采用免疫组化法检测4种MMRP(MLH1、PMS2、MSH2、MSH6)和Ki-67蛋白表达,并分析MSI、Ki-67与CRC患者临床病理特征的关系以及MSI与Ki-67表达的相关性。结果:MMRP表达缺失率为16. 7%,其中MLH1、PMS2、MSH2和MSH6的表达缺失率分别为11. 1%、11. 1%、6. 7%、4. 4%。Ki-67阳性率为90. 0%。MSI与肿瘤部位有关(P 0. 05),Ki-67表达与肿瘤部位和大体类型有关(P 0. 05)。MSI与Ki-67表达无关(P 0. 05),MLH1与PMS2表达呈正相关(r=0. 577,P 0. 05),MSH2表达与MSH6表达呈正相关(r=0. 739,P 0. 05)。结论:CRC中MLH1、PMS2表达缺失较MSH2和MSH6多见。MSI与肿瘤部位相关,Ki-67与肿瘤部位和大体类型有关,对CRC的诊疗和预后具有一定的指导意义。但MSI与Ki-67表达无关,两者联合检测并不能提高诊断CRC的准确性。     

子宫内膜异位症组织中hMLH1、hMSH2蛋白的表达及意义

目的观察人类错配修复基因h MLH1、h MSH2蛋白在子宫内膜异位症（EMS）病灶组织中的表达变化并探讨其意义。方法选择28例EMS患者的子宫内膜异位病灶组织作为病例组,其中Ⅲ期14例、Ⅳ期14例。选择因子宫肌瘤行子宫全切术的26例患者的正常子宫内膜组织作为对照组。采用免疫组化SP法检测两组h MLH1、h MSH2蛋白的表达。比较两组h MLH1、h MSH2蛋白的阳性率,比较病例组Ⅲ、Ⅳ期患者h MLH1、h MSH2蛋白的阳性率。结果病例组、对照组h MLH1蛋白阳性率分别为71.4%（20/28）、30.8%（8/26）,病例组h MLH1蛋白阳性率高于对照组（P〈0.01）。病例组、对照组h MSH2蛋白的阳性率分别为53.6%（15/28）、57.7%（15/26）,两组h MSH2蛋白表达差异无统计学意义。病例组Ⅲ、Ⅳ期患者h MLH1、h MSH2蛋白的阳性率差异无统计学意义（P均〉0.05）。结论 EMS组织h MLH1蛋白表达增高,h MLH1蛋白表达增高可能与EMS的发病有关。     

MMR与PD-L1在Ⅱ期术后结直肠癌中的差异性表达

目的探讨错配修复基因（MMR）和细胞程序性死亡配体1（PD-L1）在Ⅱ期结直肠癌（CRC）组织中的一致性及差异性。 方法选取2016年1月到2017年10月接受手术治疗的Ⅱ期CRC患者50例,免疫组化法检测术后病理组织标本中4种MMR蛋白：MutL同源蛋白1（MLH1）、Muts同源蛋白2（MSH2）、Muts同源蛋白6（MSH6）、减数分裂后分离蛋白2（PMS2）和PD-L1的表达,并分析二者的相关性。 结果结直肠癌组织中MMR缺失（dMMR）率和PD-L1的阳性率分别为32%（16/50）和38%（19/50）,dMMR和PD-L1双阳性的患者为20%（10/50）;dMMR患者中PD-L1的阳性率高于错配修复功能完整患者,62.5%（10/16）vs 26.5%（9/34）,差异具有统计学意义（χ²=5.995,P=0.027）,PD-L1的表达与MLH1和MSH2表达缺失有关（P=0.024和0.049）;PD-L1阳性患者（n=19）中dMMR与错配修复功能完整的发生率差异无统计学意义,52.6% vs 47.4%。 结论PD-L1蛋白与dMMR存在差异性表达,在使用靶向药物治疗前,应综合考虑两种生物标志物的表达情况更精准地筛选患者。     

Lynch综合征相关结直肠癌的遗传基因及分子病理筛查策略

Lynch综合征（Lynch syndrom）是结直肠癌中最常见的遗传性肿瘤综合征,约占全部大肠癌的2~3%。该病患者同时增加了罹患肠外及第二肿瘤的风险。现已证明,Lynch综合征是由于编码错配修复基因（mismatch repair,MMR）——MLH1,MSH2,MSH6和PMS2的种系突变、失活导致的一类显性遗传性疾病,近年发现EPCAM的突变与MSH2表达缺失相关。尽管有Amsterdan及Bethesda等临床诊断标准,利用分子遗传学检测在MMR基因中发现致病性胚系突变仍为目前诊断Lynch综合征的金标准。对于发病年龄小于70岁的结直肠癌患者,均应进行Lynch综合征的筛查。首先需进行微卫星不稳定性（microsatellites instability,MSI）检测,检测手段包括PCR扩增微卫星位点及免疫组化（IHC）检测,而后对相应的MMR基因进行胚系突变的检测以明确是否为Lynch综合征以及相应的致病位点。对于MLH1表达缺失患者需进行BRAF基因突变检测和（或）MLH1启动子区域甲基化检测以除外散发性结直肠癌。对于确诊的患者建议进行家系筛查并进行规律的监测和随访。     

基于Oncomine及TCGA数据集分析结肠肿瘤中HMGB1基因的表达及预后价值

目的研究结肠肿瘤中高迁移率族蛋白B1基因（HMGB1）的差异表达及预后价值。 方法从Oncomine及TCGA数据集中筛选出2 191例结肠肿瘤患者HMGB1基因表达数据及临床病理数据,采用Mann-Whitney U检验比较结肠癌与腺瘤、左半结肠癌与右半结肠癌、原位癌与浸润癌、黏液性腺癌与其他病理类型结肠癌、以及发生淋巴结转移与无淋巴结转移、发生远处转移与无远处转移结肠癌组织中HMGB1基因差异表达情况,并绘制Kaplan-Meier生存曲线。 结果HMGB1基因在结肠癌组织和腺瘤组织中均较正常结肠组织高表达（P<0.001）,在结肠癌组织中较结肠腺瘤组织中高表达,在左半结肠癌组织中较右半结肠癌高表达（P<0.05）,在黏液性腺癌组织中较其他病理类型低表达（P<0.05）,在浸润癌组织中较原位癌高表达（P<0.001）。有淋巴结转移及远处转移者较未转移者高表达（P<0.05）。HMGB1基因高表达提示更高的5年生存率（P=0.011）,尤其对于女性结肠癌患者（P=0.006）。 结论HMGB1基因可作为判断结肠癌浸润深度、淋巴转移、远处转移及预后的标志物。     

错配修复基因蛋白在散发性结直肠癌中表达的临床意义

目的探究散发性结直肠癌错配修复基因蛋白检的表达及其临床意义。方法收集150例散发性结直肠癌患者的肿瘤标本,通过免疫组织化学染色法测定错配修复基因蛋白(hPSm^2、hMLH1、hMSH6、hMSH2)水平,并分析其影响因素。结果 150例标本中有42例存在hPSm^2、hMLH1、hMSH6、hMSH2表达缺失,缺失率为28.00%,根据错配修复基因蛋白表达是否缺失分为C组(42例)和D组(108例)。经单因素分析,肿瘤部位、分化程度、BMI与错配修复基因蛋白缺失表达有关(P<0.05);经Logistic多因素回归分析,肿瘤分化程度低、位于右半结肠、BMI≥28.0与错配修复基因蛋白缺失表达有关(P<0.05)。结论散发性结直肠癌患者存在错配修复基因蛋白表达缺失现象,且表达缺失与肿瘤部位、分化程度及BMI相关,可为病情及预后评估提供依据。     

应用重叠式三角吻合技术的3D完全腹腔镜右半结肠切除术的近期疗效分析

目的比较应用重叠式三角吻合技术的3D与2D完全腹腔镜右半结肠切除术的近期疗效资料,探讨重叠式三角吻合技术在3D完全腹腔镜右半结肠切除术中的可行性和安全性。 方法回顾性分析中国医学科学院北京协和医学院肿瘤医院2017年5月至2018年10月收治的67例右半结肠恶性肿瘤患者的资料,其中行2D完全腹腔镜右半切除术的患者35例,设为2D组;行3D完全腹腔镜右半切除术的患者32例,设为3D组。对比其手术及术后恢复情况、病理情况以及围手术期并发症等。 结果两组之间,3D组手术时间、消化道重建时间明显小于2D组（均P<0.05）,但术中出血量、手术切口长度差异无统计学意义（P>0.05）。两组患者术后行走时间、排气时间、排便时间、术后住院时间差异无统计学意义（均P>0.05）。两组在肿瘤大小、远近切缘距离、淋巴结清扫数目、肿瘤TNM分期等方面,差异无统计学意义（P>0.05）。两组术后并发症发生率分别为6.2%和5.7%,差异亦无统计学意义（P=0.928）。 结论重叠式三角吻合技术在3D完全腹腔镜右半结肠切除术切实可行,安全可靠,具有满意的近期疗效。与2D腹腔镜手术相比,在3D腹腔镜下可明显缩短手术时间和消化道重建时间。     

Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome)

BACKGROUND & AIMS: The role of the mismatch repair gene PMS2 in hereditary nonpolyposis colorectal carcinoma (HNPCC) is not fully clarified. To date, only 7 different heterozygous truncating PMS2 mutations have been reported in HNPCC-suspected families. Our aim was to further assess the role of PMS2 in HNPCC. METHODS: We performed Southern blot analysis in 112 patients from MLH1-, MSH2-, and MSH6-negative HNPCC-like families. A subgroup (n = 38) of these patients was analyzed by denaturing gradient gel electrophoresis (DGGE). In a second study group consisting of 775 index patients with familial colorectal cancer, we performed immunohistochemistry using antibodies against MLH1, MSH2, MSH6, and PMS2 proteins. In 8 of 775 tumors, only loss of PMS2 expression was found. In these cases, we performed Southern blot analysis and DGGE. Segregation analysis was performed in the families with a (possibly) deleterious mutation. RESULTS: Seven novel mutations were identified: 4 genomic rearrangements and 3 truncating point mutations. Three of these 7 families fulfill the Amsterdam II criteria. The pattern of inheritance is autosomal dominant with a milder phenotype compared with families with pathogenic MLH1 or MSH2 mutations. Microsatellite instability and immunohistochemical analysis performed in HNPCC-related tumors from proven carriers showed a microsatellite instability high phenotype and loss of PMS2 protein expression in all tumors. CONCLUSIONS: We show that heterozygous truncating mutations in PMS2 do play a role in a small subset of HNPCC-like families. PMS2 mutation analysis is indicated in patients diagnosed with a colorectal tumor with absent staining for the PMS2 protein.     

Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population

PURPOSE: This clinical case review aimed to identify phenotypic variations in colorectal and extracolonic cancer expression between hereditary nonpolyposis colorectal cancer (HNPCC) families with MLH1 and MSH2 germline mutations and the general population. METHODS: Colorectal cancer onset and site distribution were compared among 67 members of MLH1 kindreds, 45 members of MSH2 kindreds, and 1,189 patients from the general population. Synchronous and metachronous cancer rates, tumor stage, extracolonic cancer incidence, and survival were also compared. RESULTS: Mean ages of colorectal cancer onset were 44, 46, and 69 years for MLH1, MSH2, and the general population, respectively (P<0.001). More proximal and fewer distal colon cancers were noted in HNPCC than the general population (P<0.001,P=0.04). Site distribution showed disparity of rectal cancers (8 percent MLH1vs. 28 percent MSH2;P=0.01) based on genotypes. Overall, synchronous colorectal cancer rates were 7.4, 6.7, and 2.4 percent for MLH1, MSH2, and the general population, respectively (P=0.016). Annual metachronous colorectal cancer rates were 2.1, 1.7, and 0.33 percent for MLH1, MSH2, and the general population, respectively (P=0.041). Colorectal cancer stage presentation was lower in HNPCC than the general population (P=0.0028). Extracolonic cancers were noted in 33 percent of MSH2 patients, compared with 12 percent of MLH1 patients and 7.3 percent of the general population with colorectal cancers (P<0.001). Combined MLH1 and MSH2 ten-year survival was 68.7 percent compared with 47.8 percent for the general population (P=0.009 stage stratified, hazard ratio 0.57). CONCLUSION: The presence of rectal cancer should not preclude the diagnosis of HNPCC, because the incidence of rectal cancer in MSH2 was comparable with that in the general population. Phenotypic variations, including the preponderance of extracolonic cancers in MSH2 patients, did not result in survival differences between genotypic subgroups. These phenotypic features of HNPCC genotypes may have clinical significance in the design of specific screening, surveillance, and follow-up for affected individuals.     

KRAS and BRAF gene mutations and DNA mismatch repair status in Chinese colorectal carcinoma patients

AIM:To investigate gene mutations and DNA mismatch repair(MMR) protein abnormality in Chinese colorectalcarcinoma(CRC) patients and their correlations with clinicopathologic features.METHODS:Clinical and pathological information for 535 patients including 538 tumors was reviewed and recorded.Mutation analyses for exon 2 of KRAS gene and exon 15 of BRAF gene were performed by Sanger sequencing except that in 9 tumors amplification refractory mutation system PCR was used.Expression of MMR proteins including MHL1,MSH2,MSH6 and PMS2 was evaluated by immunohistochemistry.Correlations of KRAS and BRAF mutation status and the expression status of MMR proteins with age,gender,cancer stage,location,and histology were analyzed.Correlations between KRAS or BRAF mutations and MMR protein expression were also explored.RESULTS:The overall frequencies of KRAS and BRAF mutations were 37.9% and 4.4%,respectively.KRAS mutations were more common in patients ≥ 50 years old(39.8% vs 22% in patients 50 years old,P 0.05).The frequencies of BRAF mutants were higher in tumors from females(6.6% vs males 2.8%,P 0.05),located in the right colon(9.6% vs 2.1% in the left colon,1.8% in the rectum,P 0.01),with mucinous differentiation(9.8% vs 2.8% without mucinous differentiation,P 0.01),or being poorly differentiated(9.5% vs 3.4% well/moderately differentiated,P 0.05).MMR deficiency was strongly associated with proximal location(20.5% in the right colon vs 9.2% in the left colon and 5.1% in the rectum,P 0.001),early cancer stage(15.0% in stages Ⅰ-Ⅱ vs 7.7% in stages Ⅲ-Ⅳ,P 0.05),and mucinous differentiation(20.2% vs 9.2% without mucin,P 0.01).A higher frequency of MLH1/PMS2 loss was found in females(9.2% vs 4.4% in males,P 0.05),and MSH2/MSH6 loss tended to be seen in younger(50 years old) patients(12.0% vs 4.0% ≥ 50 years old,P 0.05).MMR deficient tumors were less likely to have KRAS mutations(18.8% vs 41.7% in MMR proficient tumors,P 0.05) and tumorswith abnormal MLH1/PMS2 tended to harbor BRAF mutations(15.4% vs 4.2% in MMR proficient tumors,P 0.05).CONCLUSION:The frequency of sporadic CRCs having BRAF mutation,MLH1 deficiency and MSI in Chinese population may be lower than that in the Western population.     

Tissue microarray for high-throughput analysis of gene expression profiles in hepatocellular carcinoma

AIM: To study the expression profiles of HBsAg, HBcAg, p21WAF1/CIP1 (p21), Rb genes in hepatocellular carcinoma (HCC) and to investigate their roles in the hepatocar-cinogenesis. METHODS: HCC tissue microarray containing 120-min tissues of 40 HCC cases was constructed. HBsAg, HBcAg, p21 and Rb proteins were immunohistochemically stained by streptavidin-peroxidase conjugated method (S-P). The expression loss of these genes in cancerous, para-cancerous tissues and adjacent normal liver tissues of 40 HCCs were comparatively examined. RESULTS: The positive rate of HBsAg expression in cancerous tissues of 40 HCCs was 7.5%, which was lower than that in para-cancerous and adjacent normal liver tissues (X2=12.774, P<0.01; X2=18.442, P<0.01). The positive rate of HBcAg expression in cancerous tissues of 40 HCCs was 20.0%, which was also lower than that in para-cancerous and adjacent normal liver tissues (X2=9.482, P<0.01; X2=14.645, P<0.01). p21 protein deletion rate in cancerous tissues of 40 HCCs was 27.5%, which was higher than that in para-cancerous and adjacent normal liver tissues (X2=7.439, P<0.01; X2=11.174, P<0.01). p21 protein deletion correlated remarkably with the pathological grade of HCC (X2=0.072, P<0.05). Rb protein deletion rate in cancerous tissues of 40 HCCs was 42.5%, which was also higher than that in para-cancerous and adjacent normal liver tissues (X2=10.551, P<0.01; X2=18.353, P<0.01). Rb protein deletion rate did not correlate remarkably with tumor size or pathological grade of HCC (X2=0.014, P>0.05; X2=0.017, P>0.05). CONCLUSION: Expression deletion of HBsAg, HBcAg, p21 and Rb proteins in HCCs may play important roles in the carcinogenesis of HCC. Tissue microarray is an effective high-throughput technique platform for cancer research.     

Homozygous PMS2 deletion causes a severe colorectal cancer and multiple adenoma phenotype without extraintestinal cancer

BACKGROUND & AIMS: We report a patient of Indian descent with parental consanguinity, who developed 10 carcinomas and 35 adenomatous polyps at age 23 and duodenal adenocarcinoma at age 25. He also had dysmorphic features, mental retardation, and café-au-lait spots but no brain tumor. We aimed to establish his molecular diagnosis. METHODS: Germ-line screening for APC and MYH/MUTYH mutations was normal as was immunohistochemistry for MLH1 and MSH2 proteins. Investigation by array-comparative genomic hybridization revealed deletion of a small region on chromosome 7. Using polymerase chain reaction, this region was refined to a 400-kilobase deletion, which included exons 9-15 of the PMS2 gene, and all coding regions of oncomodulin, TRIAD3, and FSCN1. RESULTS: The deletion was confirmed as homozygous, and both parents were carriers. Immunohistochemistry showed absent PMS2 expression in all tumors and normal tissue. Most tumors showed microsatellite instability, more marked at dinucleotide than mononucleotide repeats. The tumors harbored no somatic mutations in APC, BRAF, AXIN2, or beta-catenin, but KRAS2 and TGFBR2 mutations were found. CONCLUSIONS: Our patient represents a novel phenotype for homozygous PMS2 mutation and perhaps the most severe colorectal cancer phenotype-in terms of numbers of malignancies at an early age-described to date. PMS2 mutations-and perhaps other homozygous mismatch repair mutations-should be considered in any patient presenting with multiple gastrointestinal tumors, since our patient could not be distinguished clinically from cases with attenuated familial adenomatous polyposis or MUTYH-associated polyposis.     

Success of referral to genetic counseling after positive lynch syndrome screening test

Purpose

Lynch syndrome (LS) is a hereditary condition that increases one’s risk of developing colorectal, endometrial, and other extracolonic cancers. MD Anderson Cancer Center at Cooper implemented a reflex screening protocol for DNA mismatch repair (dMMR) deficiency. Those with findings suspicious for LS were referred for genetic counseling (GC). Our goal was to assess compliance with GC and factors associated with successful follow-up.

Methods

Immunohistochemistry (IHC) for the MMR proteins MSH2, MLH1, MSH6, and PMS2 was performed on all colorectal tumor resections from patients ≤70 years old and all stage II cancers. Tumors with loss of MLH1/PMS2 were subsequently tested for BRAF mutation or MLH1 promoter methylation to identify tumors with likely epigenetic inactivation of MLH1. Patients with loss of MLH1/PMS2 without BRAF mutations or with absence of MLH1 promoter methylation and those with loss of MSH2/MSH6 were referred to GC. Compliance with GC was assessed.

Results

Between March 2014 and August 2016, 203 tumors were tested by IHC. Fifteen (7.4%) patients had abnormal MMR protein expression patterns in the absence of BRAF mutation or MLH1 promoter methylation suggestive of possible LS. GC compliance was 35.7% overall and 85.7% in those with family history of LS-associated cancers.

Conclusions

Overall, GC compliance was relatively low in our study. Interestingly, patients with a strong family history of LS-associated neoplasms were more likely to pursue GC. In the future, assessing and addressing barriers to seeking GC will provide opportunities to improve patient care through increased identification of patients with cancer predisposition syndromes.

     

Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer

BACKGROUND & AIMS: Germline mutations in the DNA mismatch repair (MMR) genes MSH2, MSH6, or MLH1 predispose to colorectal cancer (CRC) with an autosomal dominant inheritance pattern. The protein encoded by PMS2 is also essential for MMR; however, alterations in this gene have been documented only in extremely rare cases. We addressed this unexpected finding by analyzing a large series of CRCs. METHODS: Expression of MSH2, MSH6, MLH1, and PMS2 was studied by immunohistochemistry in 1048 unselected, consecutive CRCs. Where absence of MMR proteins was detected, microsatellite instability and cytosine methylation of the respective gene promoter were analyzed. The DNA of patients presenting with PMS2-deficient cancers was examined for germline and somatic alterations in the PMS2 gene. RESULTS: An aberrant pattern of MMR protein expression was detected in 13.2% of CRCs. Loss of expression of MSH2, MSH6, or MLH1 was found in 1.4%, 0.5%, and 9.8%, respectively. PMS2 deficiency accompanied by microsatellite instability was found in 16 cases (1.5%) with a weak family history of cancer. The PMS2 promoter was not hypermethylated in these cases. Despite interference of the PMS2 pseudogenes, we identified several heterozygous germline mutations in the PMS2 gene. CONCLUSIONS: PMS2 defects account for a small but significant proportion of CRCs and for a substantial fraction of tumors with microsatellite instability. However, the penetrance of heterozygous germline mutations in PMS2 is considerably lower than that of mutations in other MMR genes. The possible underlying causes of this unorthodox inheritance pattern are discussed.     

非小细胞肺癌中IGF1、IGFBP2表达与预后的相关性分析

目的探讨非小细胞肺癌组织胰岛素样生长因子1(IGF1)、胰岛素样生长因子结合蛋白2(IGFBP2),蛋白表达与患者临床病理特征及预后的关系。方法将226例确诊的非小细胞肺癌患者癌组织为非小细胞肺癌组;选取其癌旁正常组织为癌旁对照组。检测癌组织及癌旁正常组织IGF1、IGFBP2蛋白表达水平;分析非小细胞肺癌患者癌组织IGF1与IGFBP2蛋白表达相关性及其与预后的关系;并分析影响非小细胞肺癌患者预后的因素。结果非小细胞肺癌组IGF1、IGFBP2蛋白高表达率高于癌旁对照组(P<0.05)。非小细胞肺癌患者癌组织IGF1、IGFBP2蛋白表达与肿瘤大小、淋巴结转移、组织分化程度、TNM分期有关(P<0.05)。非小细胞肺癌患者癌组织IGF1与IGFBP2蛋白表达呈正相关(r=0.472,P<0.05)。IGF1、IGFBP2高表达患者五年生存率(33.33%、29.41%)低于低表达患者(69.23%、73.33%)(P均<0.05)。IGF1高表达、IGFBP2高表达、TNMⅢ～Ⅳ期是影响非小细胞肺癌患者死亡的独立危险因素(P<0.05)。结论 IGF1、...