DNA修复蛋白RAD52在同源重组中的作用及其在肿瘤中的研究进展

DNA损伤修复在维持细胞基因组稳定性和机体存活中发挥重要作用。DNA双链断裂（Double strandbreaks,DSBs）是DNA损伤最严重的形式。同源重组修复（homologous recombination repair，HRR）是体内参与DSBs损伤修复的重要机制之一，其中DNA修复蛋白RAD52是体内参与同源重组DNA修复的关键因子。RAD52的表达水平异常与非小细胞肺癌、胃癌、鼻咽癌、乳腺癌等肿瘤的发生、发展相关。本文对DNA修复蛋白RAD52在肿瘤研究中的应用这一热点问题进行综述。     

nm23蛋白在软组织肉瘤中的表达及意义

目的探讨nm23蛋白在软组织肉瘤中的表达及与软组织肉瘤分级的关系。方法应用FNCLCC（法国癌症中心联盟）分级系统对108例软组织肉瘤进行组织病理学分级并应用免疫组织化学技术Evision二步法检测nm23蛋白在这些肿瘤中的表达情况。结果108例软组织肉瘤中1级、2级、3级分别为23例、28例和57例;免疫组织化学染色结果显示,在1级、2级、3级中nm23蛋白的阳性表达率分别为26．1％、32．1％、61．4％,经卡方检验P〈0．05,差异有显著性。结论nm23蛋白表达与软组织肉瘤组织学分级相关并且分级越高阳性表达率越高,因此nm23在软组织肉瘤中可能扮演着促进肿瘤浸润与转移的作用。     

DNA损伤修复能力、p53蛋白及增殖细胞核抗原在大肠癌发生过程中的变化

通过检测大肠粘膜不同病变上皮细胞的非程序DNA合成（UnscheduledDNAsynthesis，UDS），分析DNA损伤修复能力，以及DNA聚合酶，突变型p53蛋白（以下简称p53蛋白）和增殖细胞核抗原（Proliferatingcellnuclearantigen，PCNA）的表达，分析这些因素在大肠癌发生过程中的变化规律。结果表明，从正常大肠粘膜，癌旁粘膜，散发性大肠腺癌到腺癌，DNA损伤修复能力依次呈逐渐下降趋势，而p53蛋白和PCVA的阳性表达率则随病变向恶性发展而呈逐渐增高的趋势。而且大肠腺癌中的阳性表达率显著高于其它病变组织。但正常粘膜与腺癌组织的DNA聚合酶β活性无显著性差异。分析了这些因素在大肠癌发病中的作用，讨论了它们之间的相互关系，并探讨某些生物标记物在肿瘤检测中的应用意义。     

DNA损伤修复基因APE1在骨肉瘤中的表达及其与血管生成的关系

目的探讨DNA损伤修复基因脱嘌呤/脱嘧啶核酸内切酶(apuinic/apyrimid-ic endonuclease,APE1)在骨肉瘤中的表达及其与肿瘤发生、发展以及血管生成的关系。方法免疫组化SP法检测三种骨肉瘤细胞株(HOS、U-2OS、Sa-OS-2)、10例正常骨、10例良性骨瘤和60例骨肉瘤组织中APE1蛋白表达,并根据CD34和FⅧ-Rag染色结果计数微血管密度(microvessel densi-ty,MVD)。结果1)APE1蛋白在三种骨肉瘤细胞株呈强阳性表达,主要定位于肿瘤细胞的胞核,60例骨肉瘤组织中43例(72%)呈高表达,17例呈低表达,且显著高于正常骨及良性骨瘤,χ2=30·997,P=0·000。2)APE1表达的程度和预后密切相关。3)APE1强表达组中的瘤内MVD为46·4±26·7,显著高于弱表达组的33·3±20·7,t=2·277,P=0·030。结论APE1在骨肉瘤中过度表达与骨肉瘤分化以及MVD密切相关,有可能作为骨肉瘤抗血管生成治疗中一个新的靶向分子。     

DNA修复基因hrad51在乳腺良、恶性病变中的表达及其生物学意义

目的　初步探讨 DNA修复基因 hrad5 1在乳腺组织病变和乳腺癌发生中的生物学意义。方法　应用S- P免疫组化法 ,分别检测了 hrad5 1蛋白在乳腺纤维腺瘤、乳腺导管上皮不典型增生、乳腺癌癌旁正常组织及乳腺癌中的表达情况。结果　 (1) hrad5 1蛋白在乳腺纤维腺瘤、导管上皮不典型增生、乳腺癌癌旁正常组织及乳腺癌中的表达率分别为 4 .0 %、13.6 %和 10 .0 %和 39.2 % ;(2 )乳腺癌中 hrad5 1蛋白的高表达与肿瘤组织分级之间 (P=0 .0 0 0 )、TNM分期之间 (P=0 .0 2 6 )呈正相关 ,与 ER的阳性表达之间 (P=0 .0 35 )呈负相关。结论　 (1) hrad5 1蛋白在不同病变乳腺组织中呈现不同表达 ,在乳腺癌组织中存在高度表达 ;(2 )检测 hrad5 1蛋白的表达情况可望成为评价乳腺癌患者预后的一个新指标     

The Prognostic Significance of Homologous Recombination Repair Pathway Alterations in Metastatic Hormone Sensitive Prostate Cancer

IntroductionThe homologous recombination repair (HRR) pathway is a frequently mutated pathway in advanced prostate cancer. The clinical course of patients with HRR gene alterations who have metastatic hormone sensitive prostate cancer (mHSPC) has not been fully characterized. Here, we examine the outcomes of men with mHSPC with HRR alterations.MethodsWe conducted a single-center retrospective analysis of men with mHSPC who underwent next generation sequencing. The primary objective was to assess the time from diagnosis of mHSPC to metastatic castrate resistance prostate cancer (mCRPC) in patients with pathogenic HRR alterations compared to individuals lacking these alterations. Key secondary objectives included time to mCRPC in prespecified cohorts, PSA response, and overall survival.Results151 men with mHSPC were identified for the study. 24% (N = 37) had pathogenic HRR gene alterations detected with the most common alterations found in BRCA2 (n = 15), ATM (n = 10), and CDK12 (n = 7). Time to mCRPC was significantly decreased in patients with HRR gene alterations versus those without such alterations (12.7 vs. 16.1 months, HR 1.95, P = .02). In multivariate analysis, the effect of HRR gene alterations on time to CRPC remained significant when adjusting for age, mHSPC therapy, the volume of disease, the presence of visceral metastases, and PSA (adjusted HR 1.69, P = .02). Stratified by specific HRR gene alteration, patients with BRCA2 or CDK12 had significantly decreased time to mCRPC compared to other HRR alterations.ConclusionHRR gene alterations are associated with the worse outcomes in mHSPC with significantly shorter time to mCRPC. Given the established role of Poly (ADP-ribose) Polymerase (PARP) inhibitors in mCRPC, these data highlight an opportunity to examine PARP inhibitors earlier in the clinical course for prostate cancer patients. Ongoing prospective studies will further validate the role of PARP inhibitors in mHSPC patients.     

DMBT1在乳腺癌组织中的表达及临床意义

[目的]探讨脑恶性肿瘤缺失基因1（DMBTI）在乳腺癌组织中的表达及意义。[方法]采用免疫组织化学方法检测73例乳腺癌组织及距其癌组织边缘2cm以上镜下未见癌浸润的正常组织中DMBT1蛋白的表达情况。[结果]免疫组织化学结果表明,DMBT1蛋白在乳腺癌组织及正常乳腺组织中的表达阳性率分别为35．6％、70．9％,差异有统计学意义（P〈0．05）。DMBT1蛋白表达与T分期、分化程度、淋巴结转移以及临床分期有关（P〈0．05）。Kap1an—Meier生存分析提示,DMBT1表达阳性的乳腺癌患者5年总生存率明显高于表达阴性者,两者比较差异具有统计学意义（P〈0．05）。[结论]乳腺癌组织中DMBT1蛋白表达降低,且与乳腺癌T分期、分化程度、淋巴结转移、临床分期及患者预后有关。     

同源重组修复缺陷与乳腺癌研究回顾及评述

摘 要：合成致死是一种新型抗肿瘤方式，基于该理论开发的第一款DNA损伤药物PARP抑制剂与同源重组修复缺陷（homologous recombination repair deficiency，HRD）形成合成致死作用，在卵巢癌、前列腺癌中显示出突破性疗效。HRD形成除了与乳腺癌遗传易感基因BRCA1/2突变有关外，还与其他同源重组修复蛋白功能的缺失有关。目前主要通过基因组瘢痕分析来评估肿瘤HRD状态。在乳腺癌中，HRD是重要的分子标志，然而相关研究进展缓慢，限制了其在乳腺癌临床实践中的应用。全文介绍HRD的形成机制、检测方法及其在乳腺癌中的研究进展及其困境，以期为乳腺癌的临床诊疗与研究设计提供新思路。     

小肠腺癌中错配修复基因hMLH1的表达及 意义

 目的探讨DNA错配修复基因hMLH1在小肠腺癌中的表达及临床意义。方法应用免疫组化SP法检测36例小肠腺癌及癌旁正常组织中hMLH1基因蛋白表达情况。结果hMLH1蛋白表达率在小肠腺癌组（66.7％）低于癌旁正常组（91.7％）,两组间差异有统计学意义（P＜0.05）。hMLH1失表达与患者年龄、性别、肿瘤部位、大小、浸润深度、有无淋巴结转移无关（P＞0.05）,但是与肿瘤分化程度密切相关（P＜0.05）,分化程度越低,hMLH1失表达越明显。结论小肠腺癌中存在MMR基因的缺陷,hMLH1基因可作为判断肿瘤分化程度的一个生物学指标。     

软组织复发及多发性平滑肌肉瘤的临床病理、免疫组织化学及电镜研究

本组报告软组织复发及多发性平滑肌肉瘤22例(多发性2例),进行了组织学、免疫组织化学及电镜观察。本组20例复发性平滑肌肉瘤复发次数为1～5次,间隔时间为2月～12年,病理可分为高分化型、低分化型、中度分化型及临界型平滑肌肉瘤。临界型易被忽略,应进行随访。     

三种DNA甲基转移酶在肝细胞癌组织中的表达及其临床意义

目的:探讨肝细胞癌组织中三种甲基转移酶(DNMT)蛋白表达的差异及其临床意义.方法:收集38例肝癌标本,取癌区组织各3块,制作组织芯片,应用免疫组化SP法分析肝癌组织中DNMT蛋白的表达,并分析其与肝癌各临床、病理参数间的关系.结果:在38例肝癌组织中,DNMT1、DNMT3a和DNMT3b蛋白的表达阳性率分别为55.3%、48.5%和65.8%.DNMT蛋白质着色主要分布在细胞核,散在分布于胞浆.DNMT1蛋白质表达与门脉癌栓和肿瘤无包膜等参数显著相关;组织中DNMT1表达与DNMT3b表达具有相关性,二者同时表达与门脉癌栓和肿瘤无包膜等参数显著相关.但三种DNMT蛋白的阳性表达与患者的年龄、性别、肿瘤分化程度和淋巴结转移无显著相关性(P>0.05).结论:肝细胞癌组织中存在三种DNMT蛋白的过表达,DNMT1和DNMT3b的高表达与门脉癌栓和肿瘤无包膜等参数显著相关,二者协同作用可能在肝癌的发生和发展中起重要作用.     

凝溶胶蛋白在胃癌组织中的表达及临床意义

目的探讨凝溶胶蛋白(gelsolin,GSN)在胃癌和癌旁组织中的表达及与其临床病理特征的关系。方法采用免疫组化法,检测28例胃癌组织中GSN表达情况。采用蛋白印迹法,检测12例胃癌组织及其对应癌旁组织中GSN表达情况。结果 GSN表达与胃癌肿瘤分化程度、TNM分期、浸润程度、淋巴结有无转移密切相关(P<0.05)。中低分化肿瘤GSN表达水平明显低于高分化肿瘤,晚期胃癌(Ⅲ+Ⅳ)中GSN表达水平明显低于早期胃癌(Ⅰ+Ⅱ),淋巴结转移患者GSN表达水平明显低于无淋巴结转移患者。结论胃癌组织中GSN表达水平明显下降,并随肿瘤进展及分化程度降低而下降,GSN在胃癌发生发展中可能起抑制作用。     

Expression and Clinical Significance of Osteopontin in Calcified Breast Tissue

Osteopontin (OPN) is an integrin-binding protein, believed to be involved in a variety of physiological cellularfunctions. The physiology of OPN is best documented in the bone where this secreted adhesive glycoprotein appearsto be involved in osteoblast differentiation and bone formation. In our study, we used semi-quantitative RT-PCRof osteopontin in calcification tissue of breast to detect breast cancer metastasis. The obtained data indicate thatthe expression of osteopontin is related to calcification tissue of breast, and possibly with the incidence of breastcancer. The expression strength of OPN by RT-PCR detection was related to the degree of malignancy of breastlesions, suggesting a close relationship between OPN and breast calcification tissue. The results revealed thatexpression of OPN mRNA is related to calcification of breast cancer tissue and to the development of breastcancer. Determination of OPN mRNA expression can be expected to be a guide to clinical therapy and predictionof the prognosis of breast cancer patients.     

Expression and Clinical Significance of ACTA2 in Osteosarcoma Tissue

Objective: To investigate the expression of alpha–smooth muscle actin (ACTA2) in osteosarcoma tissues and its relationship with prognosis. Methods: Prognostic analysis of lung metastasis–related genes in osteosarcoma using the TCGA database. Single-cell sequencing detected the expression of ACTA2 in 11 osteosarcoma tissues. Paraf- fin-embedded tissues of 74 osteosarcoma patients treated at the Sixth People’s Hospital of Shanghai Jiao Tong University from 2014 to 2019 were collected, and tissue microarrays were prepared. ACTA2 expression was detected and scored by immunohistochemistry. According to the median value of the ACTA2 histochemical score, 74 patients were divided into two groups, the high-expression group and low-expression group, and the relationship of expression with clinicopathological characteristics and prognosis was analyzed by Cox regression. Results: Through analysis of ACTA2 expression by single-cell sequencing of osteosarcoma samples together with an immuno-microarray, we found moderate ACTA2 expression. Upon analyzing the prognostic impact of ACTA2, CCL2, TGFBI, VEGFA, PDGFB, PDGFC, COL1A1, COL14A1, CXCL12, CXCL14, CSPP1, LUM, DES, MYL9, and SFRP2 on osteosarcoma patients using the TCGA database, we found that patients with high ACTA2 expression had a significantly better prognosis than those with low ACTA2 expression. Patients with high expression of ACTA2 in osteosarcoma lung metastases showed longer progression-free survival and overall survival than those with low expression. Conclusion: High expression of ACTA2 in patients with osteosarcoma lung metastasis suggests a better prognosis.