Microsatellite instability and expression of DNA mismatch repair genes in malignant astrocytic tumors from adult and pediatric patients

Microsatellite instability (MSI) is used as a molecular marker for defective DNA mismatch repair (MMR) genes.We report here alterations of MSI in 15 malignant astrocytomas (WHO grade Ⅲ) and glioblastomas (GBM; WHO grade Ⅳ) of pediatric patients (2-21 years) and 12 GBM from adults (44-68 years) by comparative analysis of BAT25/BAT26 loci and 10 other microsatellite markers. High-level microsatellite instability (MSI-H) occurred in 4 of the 15 pediatric cases (26.7%) and in 1 of the 12 adult GBM cases (8.3%). Low-level mi-

Development of a prognostic signature for esophageal cancer based on a novel 7-DNA damage repair genes signature

Esophageal cancer(EC)was an aggressive malignant neoplasm characterized by high morbidity and poor prognosis.Identifying the changes in DNA damage repair genes helps to better understand the mechanisms of carcinoma progression.In this study,by comparing EC samples and normal samples,we found a total of 132 DDR expression with a significant difference.Moreover,we revealed higher expression of POLN,PALB2,ATM,PER1,TOP3B and lower expression of HMGB1,UBE2B were correlated to longer OS in EC.In addition,a prognostic risk score based on 7 DDR gene expression(POLN,HMGB1,TOP3B,PER1,UBE2B,ATM,PALB2)was constructed for the prognosis of EC.Meanwhile,EC cancer samples were divided into 3 subtypes based on 132 DDR genes expressions.Clinical profile analysis showed cluster C1 and C2 showed a similar frequency of T2,which was remarked higher than that in cluster 3.Moreover,we found the immune cell inflation levels were significantly changed in different subtypes of EC.The infiltration levels of T cell CD8+,B cell and NK cells were greatly higher in cluster 2 than that in cluster 1 and cluster 3.The results showed T cell CD4+infiltration levels were dramatically higher in cluster 1 than that in cluster 2 and cluster 3.Finally,we perform bioinformatics analysis of DEGs among 3 subtypes of EC and found DDR genes may be related to multiple signaling,such as Base excision repair,Cell cycle,Hedgehog signaling pathway,and Glycolysis/Gluconeogenesis.These results showed DDR genes may serve as new target for the prognosis of EC and prediction of the potential response of immune therapy in EC.

Association between the DNA Repair Gene Polymorphisms and Lung Cancer in Turkish Population

Introduction: DNA repair enzymes continuously monitor DNA to correct damaged nucleotide residues generated by exposure to environmental mutagenic and cytotoxic compounds or carcinogens. Our objective was to investigate the association among XRCC1 (Arg399Gln and Arg194Trp), XRCC3 (Thr241Met), XPD-ERCC2 (Lys751Gln), APE1 (Asp241Glu), PARP-ADPRT (Val762Ala) DNA repair gene polymorphisms and lung cancer in Turkish population. Materials and Methods: Our patient group consists of 90 patients with lung cancer and the control group had 100 healthy individuals all of those smoking. DNA was extracted using the whole blood samples. PCR- RFLP technique was used to investigate the polymorphisms on target genes. Results: There was no significant difference in the genotype distributions of XPD Lys751Gln, XRCC1 Arg194Trp, XRCC3 Thr241Met, APE1 Asp241Glu between lung cancer patients and controls for each polymorphism (p > 0.05). However, there was a significant difference between the genotype distributions of XRCC1 Arg399Gln, and PARP Val762Ala in patients and the control group (p > 0.05). Discussion: Only the polymorphisms of XRCC1 codon 399 and PARP Val762Ala alleles are associated with the risk of lung cancer. Other genotypes were not related to lung cancer.

DNA repair gene XRCC1 polymorphisms and susceptibility to childhood acute lymphoblastic leukemia: a meta-analysis

Objective： To estimate the relationship between genetic polymorphisms of X-ray repair cross- complementing group 1 （XRCC1） and the susceptibility to childhood acute lymphoblastic leukemia （ALL）. Methods： Relevant case-control studies were enrolled in the meta-analysis. We applied Rev Man 4.2 software to pool raw data and test studies＇ heterogeneity and to calculate the incorporated odds ratio （OR） and 95% confidence interval （95% CI）. Results： Our data showed that the OR for the Gln allele of the Arg399Gln polymorphism, compared with the Arg allele, was 1.35 （95% CI, 1.16-1.57; P〈0.0001） for childhood ALL patients. Similarly, the homozygous genotype Gln/Gln and heterozygous genotype Arg/Gln both significantly increased the risk of childhood ALL compared with the wild genotype Arg/Arg （OR =1.58; 95% CI, 1.13-2.21; P=0.008; OR =1.51; 95% CI, 1.21-1.87; P=0.0002）. The dominant model of Arg399Gln was associated with childhood ALL risk （OR =1.54; 95% CI, 1.25-1.89; P〈0.0001）. The ethnic subgroup analysis demonstrated that the Gln allele in all five ethnic groups was prone to be a risk factor for childhood ALL just with different degrees of correlation while Arg194Trp SNP showed a protective or risk factor or irrelevant thing in different races. Conclusions： XRCC1 399 polymorphism may increase the risk of childhood ALL. Different ethnic groups with some gene polymorphism have different disease risks.

Mismatch repair gene hMSH2 protein as predictive maker for gastric carcinoma

Objective: To study the possibility of mismatch repair gene hMSH2 as a marker to predict the occurrence of gastric carcinoma. Methods: Immunohistochemical method was used to detect hMSH2 protein expressions of gastric carci- nomas (carcinoma group) and their surrounding epithelia (surrounding epithelium group) in patients and the epithelia (normal epithelium group) in persons without carcinoma. Results: The positive rates of hMSH2 protein expression in nucleus of carcinoma, surrounding epithelium and normal epithelium groups were 44.94% (71/158), 28.48% (45/158) and 11.76% (4/34), respectively (P=0.000); the positive rates of hMSH2 protein expression in plasma of the 3 groups were 37.97% (60/158), 27.85% (44/158) and 23.53% (8/34), respectively (P=0.084); the positive rates of hMSH2 protein expression in both nucleus and plasma of the 3 groups were 20.89% (33/158), 17.72% (28/158) and 2.94% (1/34), respectively (P=0.045). Although the difference of positive rates between carcinoma and surrounding epithelium groups was not significant (P=0.476), both of them were higher than that of normal epithelium group (P=0.018). Conclusion: Our findings show that the detection of hMSH2 protein expression in gastric epithelia may help to predict and diagnose gastric carcinoma.

In Vivo Improvements in Facial Appearance and in Vitro Changes in Gene Expression Using a Topical Formulation Designed to Repair Environmentally Induced DNA Damage

Background: While sunscreen has been accepted as a mainline defence against photodamage from ultraviolet, visible light and near-infrared radiation, there appears to be a lack of research into photorepair. The concept of protecting the skin during the day and repairing cellular damage at night is intuitive, yet specific strategies revolving around combinations of proven reparative active ingredients remain unelucidated. Purpose: To investigate the efficacy of a solar repair Formulation following ultraviolet and environmental exposure in order to improve overall skin health and appearance through three hypotheses: The Formulation increases expression of DNA repair mechanisms markers;The Formulation enhances overall skin appearance through reducing signs of inflammation, elevating hydration, reinforcing skin firmness and amplifying radiance;In-Vivo efficacy test results are aligned with measured gene expression changes. Methods: The Formulation (#6NIC1.V1.1-1) was tested for: In-vitro LDH cytotoxicity activity, In-vitro qPCR gene expression with and without ultraviolet exposure on a reconstructed 3-dimensional skin model, and In-Vivo efficacy study on a panel of 22 participants objectively and subjectively. Results: Skin radiance, firmness, hydration, redness, and inflammation are significantly improved after In-Vivo skin exposure to the Formulation and environmental challenges such as ultraviolet radiation. These outcomes were confirmed by in-vitro genetic testing on a reconstructed human skin model. Conclusion: The studies allowed us to identify and group results in four main skin functions that were significantly enhanced following the application of the Formulation: firmness, hydration, radiance and soothing.

Cell and gene therapy for arrhythmias： Repair of cardiac conduction damage

在 sinoatrial 节点(圣)产生的行动潜力 heart.Subsequently 统治一个健康的人的节奏和率，这些行动潜力在一个心罐头原因 arrhythmias.For 例子经由它推动产生或繁殖的传导系统 .Abnormalities 宣传到整个心，心房与心室的节点的圣机能障碍或传导块能导致当前与另外的手传导损坏可以引起的植入的电子 pacemaker.On 被对待的严肃的

CORRECTION OF DNA REPAIR GENE DEFICIENCY IN MAMMALIAN CELLS BY HUMAN HeLa S3. DNA TRANSFECTION

Study on the DNA damage and repair, especially in the mammalian cells, is one of the frontier topics in life sciences. By means of human DNA-mediated gene transfer (DMGT) method, the genes responsible for DNA repair are introduced into two kinds of repair gene defective mammalian cells. The purpose is to correct their gene deficiency and to study the mechanism of DNA damage and repair induced by radiation or alkylating agents.

Transcription-coupled repair pathway in UVC-induced SupF gene mutation in Tet-on 293 cell line

探索联合抄写的修理( TCR )的角色的目的在在在Tet上的 导致UVC 的 SupF 基因变化的小径 293 房间线，我们设计了并且构造Tet应答的 plasmid DNA pTCR-C1 ，并且利用了这 pTCR-C1 plasmid 获得记者基因在在Tet上由 UVC 导致了的 SupF 的变化频率 293 房间线。方法 SupF 基因被克隆进 Tet 应答的 plamid pBI-L，它包括一个双向 Tet 应答的倡导者，并且被称为 pTCR-C1。pTCR-C1 plasmid 是进在 Tet 上的 transfected 293 房间线，和 SupF 记者基因的变化频率当面被检测并且纪录影片的缺席。结果 pTCR-C1 plasmid 与限制消化并且 DNA 定序的方法被识别。SupF 记者基因的变化频率面对纪录影片比当纪录影片不在时高。TCR 小径在在 Tet 上参加导致 UVC 的 SupF 基因变化的结论 293 房间线。

Hypersensitive Inhibition of the Proliferation of Cells with Mutated DNA Repair-Related Genes by the Catalytic Topoisomerase II Inhibitor 20-O-IngenolEZ

We previously reported that many ingenol compounds derived from Euphoria kansui exhibit topoisomerase inhibitory activity. 20-O-ingenolEZ in these compounds exerted inhibitory effects on both topoisomerase II (topo II) activity and cell proliferative activity. Topoisomerase II inhibitors can be divided into the poison and catalytic inhibitor types and 20-O-ingenolEZ is a catalytic inhibitor and inhibits topo IIα through inhibition of ATPase activity, but induces topo II-mediated DNA damage and apoptosis in BLM-/- DT40 cells through the induction of the DNA damage checkpoint, similar to the poison type inhibitor adriamycin. The ATPase inhibitor of topo II ICRF-193 also showed poison-like characteristics in the same cell line. However, the inhibitory effects of ICRF-193 on the proliferation of BLM-/- DT40 cells differed from those of 20-O-ingenolEZ, as did the specificity of its inhibition of the proliferation of other cell lines. 20-O-ingenolEZ showed hypersensitive inhibition of the proliferation of MCF-7 cells and BLM-/- DT40 cells with mutated DNA repair-related genes.

Up-Regulated Expression of SOD2 and HPRT1 Following Topical Photoprotection and Photorepair Skincare Formulations in A 3-Dimensional Reconstructed Human Skin Model

Photodamage continues to threaten human skin health despite worldwide sun awareness campaigns and the widespread use of sunscreens. To date, extensive research is lacking into the effects of sun avoidance and solar specific skincare regimens on gene expression changes and DNA repair activity. We have previously reported that photoprotection and photorepair formulations which minimize the harmful effects of ultraviolet, visible light and near-infrared radiation can provide photoprotection, anti-photoaging benefits and rejuvenating effects optically, clinically and genetically. To investigate gene expression changes, specifically antioxidant and DNA repair effects following the use of topical photoprotection and photorepair formulations (The Essential Six, RATIONALE, Victoria, Australia), we used epidermal keratinocytes and dermal fibroblasts derived from a 3-dimensional reconstructed human skin model, and assessed upregulation of SOD2 and HPRT1. Gene expression was assessed via the Genemarkers Standard Skin Panel and quantitative real-time PCR exploration. Tissues were inoculated with solar specific topical formulations, then collected after 24 hours following application of photoprotection formulations and 16 hours following photorepair formulations. The quantitative real-time PCR revealed that, in comparison to the control, the genes encoding SOD2 and HPRT1 have been significantly up-regulated following usage of the photoprotection formulations, 1.86, and 1.41, respectively. SOD2 and HPRT1 were up-regulated following use of the photorepair formulations, 2.15, and 1.28, respectively. We were able to substantiate that the photo protection and photorepair formulations upregulated genes involved in antioxidant and DNA repair mechanisms in a 3-dimensional reconstructed human skin model, suggesting a promising anti-photoaging skin regimen. .

非小细胞肺癌组织EMSY、PIDD表达与同源重组修复基因的相关性及其临床意义

目的研究非小细胞肺癌(NSCLC)组织中EMSY转录抑制因子(EMSY)、p53诱导的死亡结构域蛋白1(PIDD)表达与同源重组修复基因表达的相关性及临床意义。方法选择2022年1月—2023年4月河北北方学院附属第一医院呼吸与危重症医学科诊治NSCLC患者80例。采用实时荧光定量PCR检测癌组织及癌旁组织中EMSY、PIDD表达与同源重组修复基因人乳腺癌易感基因1(BRCA1)、切除修复交叉互补基因1(ERCC1),核糖核苷酸还原酶亚单位1(RRM1)表达。Pearson相关分析EMSY、PIDD表达与同源重组修复基因表达的相关性;分析EMSY、PIDD表达与NSCLC临床病理相关参数的关系及在NSCLC诊断中的价值。结果NSCLC癌组织中EMSY、PIDD、BRCA1、ERCC1、RRM1 mRNA相对表达量均高于癌旁组织(t/P=30.176/<0.001,27.821/<0.001,25.075/<0.001,16.680/<0.001,25.610/<0.001)。NSCLC癌组织中EMSY、PIDD mRNA与BRCA1、ERCC1、RRM1 mRNA表达均呈正相关(r/P=0.654/<0.001,0.712/<0.001,0.584/<0.001;0.724/<0.001,0.661/<0.001,0.563/<0.001)。低分化程度、有淋巴结转移及TNM分期Ⅲ期NSCLC癌组织EMSY、PIDD mRNA表达分别显著高于高中分化程度、无淋巴结转移及TNM分期Ⅰ~Ⅱ期NSCLC癌组织(t/P=13.693/<0.001,13.380/<0.001,12.197/<0.001;10.289/<0.001,11.130/<0.001,9.405/<0.001)。EMSY、PIDD mRNA及两项联合诊断NSCLC的AUC分别为0.834、0.802、0.906,两项联合诊断的AUC大于单一指标(Z=4.751、5.257,P均<0.001)。结论EMSY、PIDD在NSCLC癌组织中表达升高,与同源重组修复基因表达及不良临床病理特征有关,两者联合有助于NSCLC的诊断。

蜚蠊改善错配修复基因缺失肠癌细胞对氟尿嘧啶敏感性的机制研究

目的:探讨中药蜚蠊改善氟尿嘧啶对错配修复基因缺失(dMMR)肠癌细胞敏感性的相关机制。方法:选择dMMR肠癌细胞,予以不同浓度氟尿嘧啶和蜚蠊作用后,利用MTT法检测两药联合的抑瘤性,根据抑制率计算出治疗指数(CI)值,明确联合增效作用,应用二代基因测序及脂质代谢分析,挖掘出差异代谢基因,数据库分析差异基因与相关机制通路。结果:中药蜚蠊可以改善氟尿嘧啶在HCT116和DLD1肠癌细胞中的疗效,GO功能富集分析和KEGG分析结果显示脂质代谢、自噬调控和凋亡通路发生主要改变,利用LC/MS进行脂质组学检测,共有153个脂质分子发生变化,包括脂肪类、鞘脂代谢物、磷脂代谢物和甘油酯。结论:蜚蠊与氟尿嘧啶联合用于dMMR肠癌细胞具有协同增效作用,可能通过调控代谢通路、自噬及凋亡通路机制改善药物疗效。

核酸切除修复途径相关基因对酿酒酵母耐受性的影响

酿酒酵母在工业发酵过程中会受到多种环境压力,包括氧化、高温、酸、乙醇及高渗等,因此选育高耐性酿酒酵母对工业生产具有重要意义。微生物中DNA重组酶、核酸修复酶等与核酸修复相关的蛋白与菌体对不良环境的耐受性有关。该实验基于核酸切除修复途径,通过基因工程手段,探究酿酒酵母内源核酸切除修复基因(RAD 16、RAD7、RAD23和RAD4)和外源基因(UVRA)对酿酒酵母耐受性的影响。结果表明,过表达酿酒酵母自身核酸切除修复基因RAD16、RAD7、RAD23及RAD4提高了酿酒酵母高渗耐受性。过表达UVRA基因可以提高菌株高渗耐受性,这意味着该元件在真核和原核细胞中存在功能上的保守性。这些结果有助于提高酿酒酵母对环境胁迫尤其是高渗透压环境的耐受性,并为研究酵母耐受性机制提供了新的思路。

ERCC1、K-ras、TP-73在替雷利珠单抗联合TP化疗方案治疗非小细胞肺癌中的评估价值

目的研究探讨核苷酸切除修复交叉互补基因1(ERCC1)、Kirsten-Rous肉瘤病毒蛋白(K-ras)、肿瘤蛋白P73(TP73)在替雷利珠单抗结合紫杉醇+顺铂(TP)化疗方案治疗NSCLC中的评估价值。方法选取2020年1月至2021年12月本院收治的126例NSCLC肺癌患者为研究对象,按随机抽签法分为对照组、观察组,各63例。对照组以TP化疗方案治疗,观察组增加替雷利珠单抗治疗。评估组间临床疗效、肿瘤标记蛋白、免疫指标、生存周期、不良反应。结果观察组患者的客观缓解率为69.84%(44/63)高于对照组患者为52.38%(33/63),观察组疾病控制率为82.54%(52/63),高于对照组患者为66.67%(42/63)(P<0.05)。化疗1周期、化疗3周期、化疗6周期时,观察组ERCC1、K-ras、TP-73水平均低于对照组(P<0.05)。治疗后观察组免疫功能补体C3、补体C4、CD40细胞低于对照组,NK细胞高于对照组(P<0.05)。观察组患者的TTP、PFS、总生存期均高于对照组(P<0.05)。观察组不良反应发生率为19.05%(12/63),对照组为12.70%(8/63),组间比较差异无统计学意义(P>0.05)。结论替雷利珠单抗联合TP化疗方案治疗肺癌有良好的治疗效果,能够改善患者免疫功能,延长患者生存周期,治疗安全性较好,且ERCC1、K-ras、TP-73水平变化可反映替雷利珠单抗联合TP化疗方案在肺癌治疗中的效果,在综合疗效评估中有较高的应用价值。

Causes and consequences of microsatellite instability in gastric carcinogenesis

Loss of DNA mismatch repair(MMR) function, due to somatic or germline epi/genetic alterations of MMR genes leads to the accumulation of numerous mutations across the genome, creating a molecular phenotype known as microsatellite instability(MSI). In gastric cancer(g C), MSI occurs in about 15% to 30% of the cases. This review summarizes the current knowledge on the molecular mechanisms underlying the acquisition of MSI in g C as well as on the clinic, pathologic and molecular consequences of the MSI phenotype. Additionally, current therapeutic strategies for g C and their applicability in the MSI subset are also discussed.

通用转录因子2I在胶质母细胞瘤替莫唑胺化疗抵抗中的作用

目的:探讨通用转录因子2I(GTF2I)在胶质母细胞瘤(GBM)替莫唑胺化疗抵抗中的作用,并阐明其作用机制。方法:基于转录因子预测网站(PROMO网站),生物信息学分析GBM组织中甲基转移酶1(DNMT1)、损伤特异性DNA结合蛋白1(DDB1)、染色盒同源物5(CBX5)和着色性干皮病基因组C(XPC)的共同转录因子,并基于癌症基因组图谱(TCGA)数据库进行DDB1、CBX5、XPC和DNMT1与GTF2I和甲基鸟嘌呤甲基转移酶(MGMT)的相关性分析及生存分析。分别用小干扰序列(siRNA)转染并沉默人脑多形性成胶质细胞瘤T98细胞和人脑胶质瘤LN229细胞中MGMT及GTF2I的基因表达,采用实时荧光定量PCR(RT-qPCR)法检测上述基因的mRNA表达水平。沉默GTF2I基因后,平板克隆形成实验检测肿瘤细胞的集落形成能力,CCK-8法检测细胞对替莫唑胺的敏感性。结果:生物信息学分析,GBM组织中DDB1、CBX5、XPC和DNMT1表达水平与GTF2I表达水平呈显著正相关关系(P<0.05),与MGMT表达水平呈负相关关系(P<0.05);GTF2I表达水平与MGMT表达水平呈显著负相关关系(P<0.05)。剔除未接受替莫唑胺治疗的GBM患者的生存分析,GTF2I高表达的患者总体生存时间降低。沉默MGMT基因后,人脑胶质瘤T98细胞中GTF2I、DDB1、CBX5和XPC mRNA表达水平升高(P<0.001);沉默GTF2I基因后,人脑胶质瘤LN229细胞中MGMT mRNA表达水平升高(P<0.05),而DDB1、CBX5、XPC和DNMT1 mRNA表达水平明显降低(P<0.05或P<0.001)。平板克隆形成实验,沉默GTF2I基因前后,细胞集落形成能力比较差异无统计学意义(P=0.138);CCK-8法检测,与对照组比较,观察组细胞活力明显降低(P<0.05)。结论:转录因子GTF2I可以调控MGMT、DDB1、CBX5和XPC等关键DNA损伤修复蛋白的mRNA表达,参与GBM细胞替莫唑胺化疗抵抗,可能是GBM潜在的治疗新靶点。

结直肠癌组织中HMGB2、MAGE-A9、MMR蛋白表达及其临床意义

目的探讨结直肠癌组织中高迁移率族蛋白B2(HMGB2)、黑色素瘤相关抗原-A9(MAGE-A9)、DNA错配修复基因(MMR)蛋白表达情况,以及其在评估患者预后中的临床价值。方法选取52例结直肠癌患者作为研究对象,术中采集所有患者肿瘤标本及癌旁组织标本,检测HMGB2、MAGE-A9、MMR蛋白表达水平,并分析各指标表达情况与病理特征、预后间的关系。结果肿瘤组织内HMGB2、MAGE-A9、MMR阳性表达高于癌旁组织,差异有统计学意义(P<0.05)。肿瘤分期Ⅲ期、分化程度低分化、淋巴结转移患者HMGB2、MAGE-A9、MMR阳性表达率高于Ⅰ期、Ⅱ期、中高分化、无淋巴结转移患者,差异有统计学意义(P<0.05)。随访3年,52例患者存活率为71.15%(37/52);HMGB2阳性组存活率[61.76%(21/34)]低于HMGB2阴性组[88.89%(16/18)],差异有统计学意义(χ^(2)=4.219,P=0.040);MAGE-A9阳性组存活率[58.62%(17/29)]低于MAGE-A9阴性组[86.96%(20/23)],差异有统计学意义(χ^(2)=5.018,P=0.025);MMR阳性组存活率[52.00%(13/25)]低于MMR阴性组[88.89%(24/27)],差异有统计学意义(χ^(2)=8.606,P=0.003)。结论HMGB2、MAGE-A9、MMR在结直肠癌中呈高表达状态,其表达与肿瘤分期、分化程度、淋巴结转移关系密切,且不同表达患者存活率存在较大差异,可作为评估预后的重要指标。

The mutation landscape of multiple cancer predisposition genes in Chinese familial/hereditary breast cancer families

Objective:Approximately 5%–10%of breast cancer(BC)patients display familial traits that are genetically inherited among the members of a family.The purpose of this study was to profile the germline mutations in 43 genes with different penetration rates and their correlations with phenotypic traits in Chinese familial BC families.Methods:Ion Torrent S5™-based next generation sequencing was conducted on 116 subjects from 27 Chinese familial BC families.Results:Eighty-one germline mutations in 27 BC predisposition genes were identified in 82.8%(96/116)of the cases.Among these,80.8%of the mutated genes were related to DNA damage repair.Fourteen possible disease-causing variants were identified in 13 of 27 BC families.Only 25.9%(7/27)of the BC families exhibited hereditary deficiency in BRCA1/2 genes,while 22.2%of the BC families exhibited defects in non-BRCA genes.In all,41.7%(40/96)of the mutation carriers had BRCA mutations,88.5%(85/96)had non-BRCA mutations,and 30.2%(29/96)had both BRCA and non-BRCA mutations.The BC patients with BRCA mutations had a higher risk of axillary lymph node metastases than those without mutations(P<0.05).However,the BC patients with non-BRCA mutations frequently had a higher occurrence of benign breast diseases than those without mutations(P<0.05).Conclusions:In addition to BRCA1/2,genetic variants in non-BRCA DNA repair genes might play significant roles in the development of familial/hereditary BC.Therefore,profiling of multiple BC predisposition genes should be more valuable for screening potential pathogenic germline mutations in Chinese familial/hereditary BC.

结直肠癌组织中MMR蛋白表达、MSI、RAS和BRAF基因突变与临床病理特征的关系

目的 探讨结直肠癌患者癌组织中错配修复(MMR)蛋白表达、微卫星不稳定性(MSI)、大鼠肉瘤(RAS)基因和致癌同源体B1(BRAF)基因突变与临床病理特征的关系。方法 选取该院2022年1-12月接受根治手术治疗的352例结直肠癌患者的肿瘤组织和血液标本、42例非肠癌患者的实体瘤组织和血液标本,采用免疫组化法检测MMR蛋白表达,一代测序片段分析法检测MSI,实时荧光定量聚合酶链反应检测KRAS、NRAS和BRAF基因突变状态,分析MMR蛋白表达、MSI和3种基因突变状态与结直肠癌临床病理特征的关系。结果 352例CRC患者肿瘤组织中检出MMR缺陷(dMMR)29例(8.2%),高度微卫星不稳定(MSI-H)26例(7.4%),KRAS基因突变161例(45.7%),NRAS基因突变13例(3.7%),BRAF基因突变11例(3.1%)。与dMMR有关因素为低龄、黏液腺癌、原发于右半结肠癌(P<0.05);与MSI-H相关因素包括低龄、肿瘤家族史、原发于右半结肠癌(P<0.05);KRAS和NRAS基因高突变率分别与黏液腺癌和淋巴结转移有关(P<0.05);BRAF基因高突变率与低分化和原发于右半结肠癌有关(P<0.05)。BRAF基因突变与dMMR和MSI-H有关(P<0.05)。结论 MMR蛋白表达,MSI,以及KRAS、NRAS和BRAF基因突变与不同的临床病理特征有关。通过这5种分子标志物的联合检测可以对肿瘤进行分子分型,进一步为结直肠癌患者的个体化精准诊疗提供理论依据。