Mismatch repair gene germline mutations in patients with prostate cancer / 浙江大学学报·医学版

OBJECTIVES@#To investigate the prevalence of pathogenic germline mutations of mismatch repair (MMR) genes in prostate cancer patients and its relationship with clinicopathological characteristics.@*METHODS@#Germline sequencing data of 855 prostate cancer patients admitted in Fudan University Shanghai Cancer Center from 2018 to 2022 were retrospectively analyzed. The pathogenicity of mutations was assessed according to the American College of Medical Genetics and Genomics (ACMG) standard guideline, Clinvar and Intervar databases. The clinicopathological characteristics and responses to castration treatment were compared among patients with MMR gene mutation (MMR+ group), patients with DNA damage repair (DDR) gene germline pathogenic mutation without MMR gene (DDR+MMR－ group) and patients without DDR gene germline pathogenic mutation (DDR－ group).@*RESULTS@#Thirteen (1.52%) MMR+ patients were identified in 855 prostate cancer patients, including 1 case with MLH1 gene mutation, 6 cases with MSH2 gene mutation, 4 cases with MSH6 gene mutation and 2 cases with PMS2 gene mutation. 105 (11.9%) patients were identified as DDR gene positive (except MMR gene), and 737 (86.2%) patients were DDR gene negative. Compared with DDR－ group, MMR+ group had lower age of onset (P<0.05) and initial prostate-specific antigen (PSA) (P<0.01), while no significant differences were found between the two groups in Gleason score and TMN staging (both P>0.05). The median time to castration resistance was 8 months (95%CI: 6 months-not achieved), 16 months (95%CI: 12-32 months) and 24 months (95%CI: 21-27 months) for MMR+ group, DDR+MMR－ group and DDR－ group, respectively. The time to castration resistance in MMR+ group was significantly shorter than that in DDR+MMR－ group and DDR－ group (both P<0.01), while there was no significant difference between DDR+MMR－ group and DDR－ group (P>0.05).@*CONCLUSIONS@#MMR gene mutation testing is recommended for prostate cancer patients with early onset, low initial PSA, metastasis or early resistance to castration therapy.

Polimorfismos en genes de reparación del daño al material genético y cáncer de pulmón

RESUMEN Introducción: El cáncer de pulmón es uno de los principales problemas de salud en Cuba y el mundo. Las diferencias genéticas a causa de polimorfismos de un solo nucleótido, son factores importantes involucrados en la susceptibilidad genética a esta enfermedad. En Cuba son escasos los datos disponibles sobre los polimorfismos de un solo nucleótido y su posible influencia sobre la aparición y pronóstico del cáncer. Objetivo: Exponer la importancia del estudio de los polimorfismos de un solo nucleótido en genes de la reparación del daño al ADN en el cáncer de pulmón. Desarrollo: El tabaquismo es el principal factor de riesgo para desarrollar cáncer de pulmón, sin embargo, aproximadamente el 15 % de los fumadores desarrollará la enfermedad. Los polimorfismos de un solo nucleótido son factores involucrados en la predisposición genética a las enfermedades. La presencia de variantes polimórficas puede modificar la eficacia de los sistemas de reparación, favoreciendo la aparición de genotoxicidad y/o mutagénesis. También pueden modificar la respuesta a los tratamientos oncológicos y la supervivencia de los pacientes. Por consiguiente, además de ser marcadores de susceptibilidad, los polimorfismos se consideran marcadores de pronóstico individual de respuesta a la terapia. Este trabajo enfatiza la utilidad de su evaluación como biomarcadores clínicos y de susceptibilidad genética a enfermedades en la población cubana. Conclusiones: El estudio de polimorfismos de un solo nucleótido permitirá el abordaje personalizado de enfermedades oncológicas, lo cual podría contribuir a su detección temprana y a definir grupos de individuos con alto riesgo de padecer cáncer de pulmón.

ABSTRACT Introduction: Lung cancer is one of the main health problems in Cuba and worldwide. Genetic differences due to single nucleotide polymorphisms are important factors involved in the genetic susceptibility to this disease. In Cuba, there are scarce data available on single nucleotide polymorphisms and their possible influence on the incidence and prognosis of cancer. Objective: To expose the importance of the study of single nucleotide polymorphisms in DNA damage repair genes in lung cancer. Results: Smoking is the main risk factor for developing lung cancer, however, approximately 15 % of smokers will develop the disease. Single nucleotide polymorphisms are important factors involved in genetic predisposition to diseases. The presence of polymorphic variants can modify the efficacy of repair systems, favoring the occurrence of genotoxicity and/or mutagenesis. They can also modify the response to oncological treatments and patient´s survival. Therefore, in addition to being susceptibility markers, polymorphisms are considered individual prognostic markers of response to therapy. This work emphasizes the usefulness of evaluating single nucleotide polymorphisms as clinical and susceptibility biomarkers in the Cuban population. Conclusions. The study of single nucleotide polymorphisms will allow a personalized approach to oncological diseases, which could contribute to define groups of individuals at high risk of getting lung cancer, therefore, early disease detection.

Predictive value of DNA repair gene expression for response to neoadjuvant chemotherapy in breast cancer

Genome-wide analysis using microarrays has revolutionized breast cancer (BC) research. A substantial body of evidence supports the clinical utility of the 21-gene assay (Oncotype DX) and 70-gene assay (MammaPrint) to predict BC recurrence and the magnitude of benefit from chemotherapy. However, there is currently no genetic tool able to predict chemosensitivity and chemoresistance to neoadjuvant chemotherapy (NACT) during BC treatment. In this study, we explored the predictive value of DNA repair gene expression in the neoadjuvant setting. We selected 98 patients with BC treated with NACT. We assessed DNA repair expression in 98 formalin-fixed, paraffin-embedded core biopsy fragments used at diagnosis and in 32 formalin-fixed, paraffin-embedded post-NACT residual tumors using quantitative reverse transcription-polymerase chain reaction. The following genes were selected: BRCA1, PALB2, RAD51C, BRCA2, ATM, FANCA, MSH2, XPA, ERCC1, PARP1, and SNM1. Of 98 patients, 33 (33.7%) achieved pathologic complete response (pCR). The DNA expression of 2 genes assessed in pre-NACT biopsies (PALB2 and ERCC1) was lower in pCR than in non-pCR patients (P=0.005 and P=0.009, respectively). There was no correlation between molecular subtype and expression of DNA repair genes. The genes BRCA2 (P=0.009), ATM (P=0.004), FANCA (P=0.001), and PARP1 (P=0.011) showed a lower expression in post-NACT residual tumor samples (n=32) than in pre-NACT biopsy samples (n=98). The expression of 2 genes (PALB2 and ERCC1) was lower in pCR patients. These alterations in DNA repair could be considered suitable targets for cancer therapy.

Extensive colectomy in colorectal cancer and hereditary nonpolyposis colorectal cancer - long-term results / Colectomia extensa em cancro colorretal e cancro colorretal hereditário sem polipose - resultados a longo prazo

ABSTRACT Background: Colorectal cancer survival is better in hereditary nonpolyposis colorectal cancer patients than in sporadic colorectal cancer patients and even for hereditary nonpolyposis colorectal cancer with colorectal cancer is not consensual that extensive colectomy is preferable to partial colectomy. This study analyzes and compares the long-term results of these two groups of patients submitted to curative subtotal colectomy or total colectomy. Methods: Between 2002 and 2018, 68 patients with colorectal cancer without familial adenomatous polyposis were submitted to a total or subtotal colectomy in a single tertiary center. The patients were divided in two groups: hereditary nonpolyposis colorectal cancer patients (with Amsterdam criteria) and sporadic colorectal cancer patients (the others). The presence of Amsterdam criteria for hereditary nonpolyposis colorectal cancer and germline mutation for mismatch repair genes was confirmed by clinical records. Results and survival were analyzed following surgery. Results: We obtained a sporadic colorectal cancer group with 31 patients and a hereditary nonpolyposis colorectal cancer group with 37 patients. The two groups differ in age but not in gender, tumor stage or surgical morbidity. The overall survival and disease-free survival were good in both groups but even better for hereditary nonpolyposis colorectal cancer group with statistical significance when comparing the two groups. Conclusion: Total or subtotal colectomy for colorectal cancer provides a good survival. These surgical procedures should be considered the first option for colorectal cancer in young hereditary non polyposis colorectal cancer patients. In those cases, they provide good long-term results, avoiding the risk of metachronous colorectal cancer and the surveillance is restricted only to the remaining need for rectum.

RESUMO Introdução: A sobrevivência do cancro colorretal é melhor em pacientes com cancro colorretal hereditário não associado a polipose do que em pacientes com cancro colorretal esporádico. Mesmo em casos de cancro colorretal hereditário sem polipose, a preferência pela colectomia total em relação à parcial não é consensual na literatura. Este estudo analisa e compara os resultados a longo prazo destes dois grupos de pacientes submetidos à colectomia curativa subtotal ou total. Métodos: Entre 2002 e 2018, 68 pacientes com cancro colorretal sem polipose adenomatosa familiar foram submetidos a colectomia total ou subtotal em um único centro terciário. Os pacientes foram divididos em dois grupos: aqueles com cancro colorretal hereditário sem polipose (de acordo com os critérios de Amsterdão) e os com cancro colorretal esporádico (os demais). Os critérios de Amsterdão para cancro colorretal hereditário sem polipose e a presença de mutação germinativa para os genes de reparação de ADN foram confirmados por consulta dos registros clínicos. Os resultados e a sobrevivência foram analisados após a cirurgia. Resultados: No presente estudo, 31 pacientes foram incluídos no grupo de cancro colorretal esporádico e 37 no grupo de cancro colorretal hereditário sem polipose. Diferenças significativas foram observadas em relação à idade, mas não ao gênero, estadio do tumor ou morbilidade cirúrgica. A sobrevivência global e a sobrevivência livre de doença foram boas em ambos os grupos, mas os resultados foram ainda melhores no grupo de cancro colorretal hereditário sem polipose, com significado estatístico. Conclusão: A colectomia total ou a colectomia subtotal para o cancro colorretal proporcionam uma boa sobrevivência e devem ser consideradas a primeira opção de tratamento em pacientes jovens com cancro colorretal hereditário sem polipose. Nestes pacientes, uma cirurgia cólica mais extensa permite a obtenção de bons resultados a longo prazo; reduz o risco de cancro colorretal metácrono e restringe a vigilância endoscópica ao reto remanescente.

Epigenética del cáncer colorrectal / Epigenetics of Colorectal Cancer

Resumen El cáncer colorrectal (CCR) es una enfermedad con una amplia distribución geográfica, que afecta a millones de personas en el mundo. Esta neoplasia se presenta de manera esporádica en el 80% de los casos, el porcentaje restante tiene una historia familiar. Las alteraciones epigenéticas, como la metilación del ADN, modificación de las histonas y los ácidos ribonucleicos (ARN) no codificantes, están involucradas en el desarrollo de esta enfermedad. En la actualidad, estas alteraciones tienen un potencial valioso como biomarcadores para la detección temprana del CCR y se considera que podrían ser útiles para el diagnóstico y pronóstico de los individuos con CCR. El propósito de esta revisión es describir los principales mecanismos epigenéticos involucrados en el cáncer colorrectal, que tienen una función importante en el desarrollo y progresión de la enfermedad.

Abstract Colorectal cancer (CRC) has broad geographic distribution and affects millions of people throughout the world. It occurs sporadically in 80% of cases, but the rest have family histories. Epigenetic alterations such as DNA methylation and modification of histones and non-coding RNA are involved in the development of this disease. At present, these alterations have valuable potential as biomarkers for early detection of CRC and could be useful for diagnosis and determination of prognosis for individuals with CRC. The purpose of this review is to describe the main epigenetic mechanisms involved in colorectal cancer and the important roles they have in the development and progression of the disease.

Screening for lynch syndrome in endometrial carcinoma / 临床与实验病理学杂志

Purpose To evaluate the application of mismatch repair (MMR) genes proteins expression and methylationspecific to screen for Lynch syndrome patients.Methods 126 endometrial carcinoma patients were tested the protein expression of hMSH2,hMSH6h,hMLH1,hPMS2 by immunohistochemically of SP,and the methylation status of hMLH1 genes by the methylation-specific PCR.Results The result of MMR immunocytochemistry showed that 22％ (28/126) cases lacked MMR protein expression,including hMLH1-/hPMS2-in 12 cases,4 hMSH2-/hMSH6-,6 hPMS2-,3 hMLH6-and 3 hMLH1-.Meanwhile,the methylation-specific PCR test showed that 9 cases was methylation status of hMLH1 genes in 15 cases hMLH1-,and suggested the patients might be sporadic endometrial carcinoma.Conclusion Immunohistochemical of SP staining for MMR proteins in endometrial carcinoma patients,accompanied by testing for the methylation status of hMLH1 genes,may be an effective approach to screen for Lynch syndrome.

Single nucleotide polymorphisms in DNA repair genes and the association of DNA damage with age-related cataract / 眼科新进展

Objective To examine the association of 18 single nucleotide polymorphisms (SNPs) in 4 DNA repair genes (BLM,WRN,ERCC6 and OGG1) with age-related cataract (ARC) in a Han Chinese population from Jiangsu Eye Study and to determine the possible functional consequence of the SNPs to DNA damage.Methods Together 18 SNPs in 4 DNA repair genes were genotyped in 789 ARC patients and 531 normal controls from Jiangsu Eye Study.The Comet assay was conducted to assess the extent of DNA damage in peripheral lymphocytes of the selected subjects.Results The results showed that WRN-rs11574311 was initially associated with ARC in general,cortical and mixed cataracts (P =0.003,OR =1.49;P =0.001,OR =1.68 and P ＜0.000 1,OR=2.08),BLM-rs1063147 with nuclear cataracts (P =0.03,OR =1.31),WRN-rs2725383 with cortical cataracts (P =0.01,OR =1.49),WRN-rs4733220 and WRN-rs2725338 with mixed cataracts (P =0.04,OR =0.74 and P =0.003,OR =0.60).However,after Bonferroni corrections,WRN-rs11574311 was still associated with cortical and mixed cataracts,as well as WRN-rs2725338 with mixed cataracts.The difference in DNA damage of peripheral lymphocytes with SNP types did not approach statistical significance among groups (all P ＞ 0.05).Conclusion WRN genes may have a vital role in ARC pathogenesis and exert a different action in ARC subtypes,which may be associated with different risk factors and mechanisms.

Expression of the Four Mismatch Repair Genes Protein of Patients with Colorectal Cancer and Its Clinical Significance / 现代生物医学进展

Objective:To analyze the expression of the four mismatch repair genes protein (hMLH1,hMSH2,hMSH6 and hPMS2) of patients with colorectal cancer and its clinical significance.Methods:177 cases of patients with colorectal caner in the Third Affiliated Hospital of Guangzhou Medical University from January 2013 to December 2015 were randomly selected.Tested the expression of the hMLH1,hMSH2,hMSH6 and hPMS2 by immunohistochemistry,the relationship between protein expression and clinical parameters was analyzed.Results:Among 177 cases ofcolorectal cancer tissue,the deletion rate ofhMLH1 protein was 6.2％ (11/177),the deletion rate of hMLH2 protein was 4.0％(7/177),the deletion rate of hMSH6 protein was 1.7％(3/177),the deletion rate of hPMS2 protein was 8.0％(14/177),the sum of the four values accounted for 19.8％(35/177) of all cases of colorectal cancer.The loss of expression of the four mismatch repair genes protein were correlated to tumor location (P＜0.05),besides,the loss of expression of the hMLH1 and hPMS2 protein were correlated to degree of tumor differentiation (P＜0.05),he loss of expression of the hMSH6 protein were correlated to depth of tumor invasion(P＜0.05);But the loss was not correlated to age,sexes,lymph node metastasis and distant metastasis(P＞0.05).Conclusion:The expression of loss phenomenon with mismatch repair protein appears in part of colorectal cancer,the loss phenomenon with mis match repair protein were correlated to tumor location and degree of tumor differentiation.Mutations of four genes in hMLH1,hPMS2,hMSH6 and bMSH2,to provide a reference value for the clinical judgment of prognosis and to develop a treatment plan.

Early onset of colorectal cancer in a 13-year-old girl with Lynch syndrome / 소아과

Lynch syndrome is the most common inherited colon cancer syndrome. Patients with Lynch syndrome develop a range of cancers including colorectal cancer (CRC) and carry a mutation on one of the mismatched repair (MMR) genes. Although CRC usually occurs after the fourth decade in patients with Lynch syndrome harboring a heterozygous MMR gene mutation, it can occur in children with Lynch syndrome who have a compound heterozygous or homozygous MMR gene mutation. We report a case of CRC in a 13-year-old patient with Lynch syndrome and congenital heart disease. This patient had a heterozygous mutation in MLH1 (an MMR gene), but no compound MMR gene defects, and a K-RAS somatic mutation in the cancer cells.

Multiple gene sequence analysis using genes of the bacterial DNA repair pathway

The ability to recognize and repair abnormal DNA structures is common to all forms of life. Physiological studies and genomic sequencing of a variety of bacterial species have identified an incredible diversity of DNA repair pathways. Despite the amount of available genes in public database, the usual method to place genomes in a taxonomic context is based mainly on the 16S rRNA or housekeeping genes. Thus, the relationships among genomes remain poorly understood. In this work, an approach of multiple gene sequence analysis based on genes of DNA repair pathway was used to compare bacterial genomes. Housekeeping and DNA repair genes were searched in 872 completely sequenced bacterial genomes. Seven DNA repair and housekeeping genes from distinct metabolic pathways were selected, aligned, edited and concatenated head-to-tail to form a super-gene. Results showed that the multiple gene sequence analysis using DNA repair genes had better resolution at class level than the housekeeping genes. As housekeeping genes, the DNA repair genes were advantageous to separate bacterial groups at low taxonomic levels and also sensitive to genes derived from horizontal transfer.

A resistência das células T98G e U87MG à temozolamida está correlacionada com a expressão de genes de reparo de DNA / The resistance of T98G and U87MG cell lines to temozolomide is correlated with the expression of DNA repair genes

Os gliomas são tumores cerebrais definidos patologicamente pela presença de células com características histológicas e imuno-histoquímicas que evidenciam diferenciação glial. Dentre eles, os astrocitomas são os mais frequentes em adultos. Estes tumores normalmente apresentam infiltração difusa no tecido adjacente, são resistentes aos tratamentos e têm uma tendência natural para a progressão maligna. O tratamento padrão atual consiste na realização de ressecção cirúrgica do tecido tumoral seguida de radio e quimioterapia concomitantes, porém o prognóstico permanece extremamente pobre. O quimioterápico padrão-ouro no tratamento de GBM é o agente alquilante de DNA temozolamida (TMZ). Entretanto, os danos induzidos pela TMZ podem ser revertidos pela ação da maquinaria de reparo de DNA, impedindo a morte celular e levando à resistência do GBM ao tratamento. No presente estudo correlacionamos a expressão dos genes ATM, BRCA2, BRIP1, EXO1, NEIL3, RAD54L e XRCC2, envolvidos em reparo de DNA e sabidamente superexpressos em GBM, com a resistência das linhagens celulares T98G e U87MG ao tratamento com TMZ. Mostramos que a linhagem T98G é a mais resistente ao tratamento com TMZ, e apresenta superexpressão de BRCA2, BRIP1, EXO1, NEIL3, RAD54L e XRCC2 e sub-expressão de ATM. Vimos também que a linhagem U87MG, mais sensível ao tratamento com TMZ, apresenta expressão reduzida dos genes ATM, BRCA2 e EXO1. Portanto, estes dados sugerem uma correlação positiva entre a expressão de genes de reparo de DNA e a resistência das células de GBM à TMZ.(AU)

Gliomas are brain tumors pathologically defined by the presence of cells with histological and immunohistochemical characteristics of glial differentiation. Among them, astrocytomas are the most common in adults. These tumors usually show diffuse infiltration into adjacent tissue, are resistant to treatment and have a natural tendency to malignant progression. The current standard treatment consists in surgical removal of the tumor followed by radiotherapy and concurrent chemotherapy. However, the prognosis remains extremely poor. The first line chemotherapy for GBM treatment is the DNA alkylating agent temozolamide (TMZ). Nevertheless, TMZ-induced damage can be reversed by the action of DNA repair machinery that prevents cell death and leads to relapse. In this study we correlated the expression of the DNA damage-signaling gene, ATM kinase, and the DNA repair genes BRCA2, BRIP1, EXO1, NEIL3, RAD54L and XRCC2, with the resistance of T98G and U87MG cell lines to TMZ. T98G cells were more resistant to TMZ treatment and showed overexpression of all DNA repair genes, while ATM kinase was down regulated. We also observed that U87MG cells, more sensitive to TMZ, have reduced expression of ATM, BRCA2 and EXO1. Therefore, these data suggest a positive correlation between the expression of DNA repair genes and the resistance of GBM cells to TMZ.(AU)

Effect of cisplatin and paclitaxel on the cytotoxicity of cytokine-in-duced killer cells on esophagus carcinoma and its molecular mecha-nisms / 中国肿瘤临床

Objective:To explore the effect of paclitaxel (PTX) and cisplatin (DDP) on the expression of NKG2D ligands of hu-man esophagus carcinoma cell EC9706 and on the cytotoxicity of cytokine-induced killer (CIK) cells, as well as to discuss its molecu-lar mechanisms. Methods: The half maximal inhibitory concentration (IC50) values of PTX and DDP against EC9706 cells for 24 h were measured by MTT assay. The expression levels of NKG2D ligands (MICA, MICB, ULBP1, ULBP2, and ULBP3) on the EC9706 cell surface before and after 24 h culture with 1/2 IC50 of PTX or DDP were assayed by flow cytometry. Cytotoxicity of CIK cells against EC9706 cells before and after 24 h culture with 1/2 IC50 PTX or DDP was analyzed by lactate dehydrogenase release assay at an effector to target cell ratio (E:T) of 20:1 and 30:1, respectively. The expression levels of DNA damage repair genes (ATM, ATR, CHK1, CHK2, and p53) of EC9706 cells before and after 24 h incubation with 1/2 IC50 PTX or DDP were detected by quantitative fluorescent PCR. Results:The IC50 values of PTX and DDP were 10 and 5μg/mL, respectively. MICB, ULBP2, and ULBP3 on EC9706 cells were upregulated after 24 h culture with 1/2 IC50 PTX (P0.05), whereas ATM, ATR, CHK1, and CHK2 were over-expressed after 24 h treatment with 1/2 IC50 DDP (P<0.05). Conclusion:PTX or DDP can enhance the susceptibility of EC9706 cells to CIK cell-mediated lysis by upregulating the expression of NKG2D ligands through activating DNA damage repair genes.

Constitutional mismatch repair deficiency syndrome: Do we know it.

Constitutional mismatch repair deficiency syndrome is a rare autosomal recessive syndrome caused by homozygous mutations in mismatch repair genes. This is characterized by the childhood onset of brain tumors, colorectal cancers, cutaneous manifestations of neurofibromatosis‑1 like café au lait spots, hematological malignancies, and occasionally other rare malignancies. Here, we would like to present a family in which the sibling had glioblastoma, and the present case had acute lymphoblastic lymphoma and colorectal cancer. We would like to present this case because of its rarity and would add to literature.

Differential expression of thymic DNA repair genes in low-dose-rate irradiated AKR/J mice

We previously determined that AKR/J mice housed in a low-dose-rate (LDR) (137Cs, 0.7 mGy/h, 2.1 Gy) gamma-irradiation facility developed less spontaneous thymic lymphoma and survived longer than those receiving sham or high-dose-rate (HDR) (137Cs, 0.8 Gy/min, 4.5 Gy) radiation. Interestingly, histopathological analysis showed a mild lymphomagenesis in the thymus of LDR-irradiated mice. Therefore, in this study, we investigated whether LDR irradiation could trigger the expression of thymic genes involved in the DNA repair process of AKR/J mice. The enrichment analysis of Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways showed immune response, nucleosome organization, and the peroxisome proliferator-activated receptors signaling pathway in LDR-irradiated mice. Our microarray analysis and quantitative polymerase chain reaction data demonstrated that mRNA levels of Lig4 and RRM2 were specifically elevated in AKR/J mice at 130 days after the start of LDR irradiation. Furthermore, transcriptional levels of H2AX and ATM, proteins known to recruit DNA repair factors, were also shown to be upregulated. These data suggest that LDR irradiation could trigger specific induction of DNA repair-associated genes in an attempt to repair damaged DNA during tumor progression, which in turn contributed to the decreased incidence of lymphoma and increased survival. Overall, we identified specific DNA repair genes in LDR-irradiated AKR/J mice.

Expression of mismatch repair genes hMLH1 and hMSH2 and their significance in patients with colorectal carcinoma / 中国肿瘤临床

10.3969/j.issn.1000-8179.2013.12.007

DNA Repair Genes XRCC1, XRCC3, XPD, and OGG1 Polymorphisms among the Central Region Population of Saudi Arabia

DNA repair is one of the central defense mechanisms against mutagenic exposures. Inherited SNPs of DNA repair genes may contribute to variations in DNA repair capacity and susceptibility to cancer. Due to the presence of these variants, inter-individual and ethnic differences in DNA repair capacity have been established in various populations. Saudi Arabia harbors enormous genetic and cultural diversity. In the present study we aimed to determine the genotype and allele frequencies of XRCC1 Arg399Gln (rs25487), XRCC3 Thr241Met (rs861539), XPD Lys751Gln (rs13181), and OGG1 Ser326Cys (rs1052133) gene polymorphisms in 386 healthy individuals residing in the central region of Saudi Arabia and compare them with HapMap and other populations. The genotype and allele frequencies of the four DNA repair gene loci in central Saudi population showed a distinctive pattern. Furthermore, comparison of polymorphisms in these genes with other populations also showed a unique pattern for the central Saudi population. To the best of our knowledge, this is the first report that deals with these DNA repair gene polymorphisms among the central Saudi population.

Modification of histone acetylation and its regulation effect to the expression of mismatch repair genes in acute leukemia / 白血病·淋巴瘤

Objective To explore the status of histone acetylation modification and their regulatory effect to hMSH2 gene and hMLH1 gene expression in acute leukemia. Methods Reverse transcription-polymerase chain reaction (RT-PCR) was used to measure the expression of hMSH2 and hMLH1 mRNA, and Western blot was used to measure the expression of histone H3, H4, HDACi, hMSH2 and hMLH1 protein in mononuclear cells of 56 acute leukemia patients and 30 healthy volunteers. The mononuclear cells of 30 acute leukemia patients were treated with histone deacetylase inhibitors trichostatin A (TSA), and measured the expression difference of histone H3, H4, HDAC1, hMSH2 and hMLH1 in the mononuclear cells treated with TSA. Results The protein expression levels of hMSH2, hMLH1, histone H3 and histone H4 in those mononuclear cells of acute leukemia patients were 0.4610±0.1211, 0.4013±0.1143, 0.4103±0.1241 and 0.4251±0.1081, respectively, which were significantly decreased comparing with those of healthy volunteers (0.9461±0. 1841, 0.996±0.2021, 0.8971±0. 1194 and 0.9513±0.1953) (t = 3.341, 3.935, 2.843 and 3.575,respectinely, P ＜0.05). The protein expression levels of HDAC1 (0.8841±0.2018) of acute leukemia patients was significantly increased comparing with those of healthy volunteers (0.5142±0.1340) (t= 2.634, P ＜0.05).After treatment with TSA for 48 hours, the protein expression of hMSH2 was increased nearly 1.5-fold, hMLH1 about 1.6-fold, H3 about 2.9-fold and H4 about 3.4-fold comparing with the negative control groups (P ＜0.05),while the protein expression of HDAC1 were decreased comparing with the negative control groups by 40 %.Conclusion There was an low expression phenomenon of histone acetylation in acute leukemia, and histone acetylation played an important role in regulation of the mismatch repair gene expression in acute leukemia.

Alterations in DNA repair gene expression and their possible regulation in rat-liver regeneration

Rapidly proliferating tissue may require enhanced DNA repair capacity in order to avoid fixation of promutagenic DNA lesions to mutations. Partial hepatectomy (PH) triggers cell proliferation during liver regeneration (LR). However, little is known on how DNA repair genes change and how they are regulated at the transcriptional level during LR. In the present study, the Rat Genome 230 2.0 array was used to detect the expression profiles of DNA repair genes during LR, and differential expression of selected genes was confirmed by real-time RT-PCR. 69 DNA repair genes were found to be associated with LR, more than half of which distributed in a cluster characterized by a gradual increase at 24-72h and then returning to normal. The expression of base excision repair- and transcription-coupled repair-related genes was enhanced in the early and intermediate phases of LR, whereas the expression of genes related to HR, NHEJ and DNA cross-link repair, as well as DNA polymerases and related accessory factors, and editing or processing nucleases, were mainly enhanced in the intermediate phase. The expression changes of genes in DNA damage response were complicated throughout the whole LR. Our data also suggest that the expression of most DNA repair genes may be regulated by the cell cycle during LR.

Effect of 5-Aza-2’-deoxycytidine on cell apoptosis in ovarian cancer cell line and expression of HMLH1 as well as HMSH2 / 基础医学与临床

Objective To observe the effects of 5-Aza-2’-deoxycytidine(5-Aza-CdR)on cell proliferation and apoptosis in ovarian cancer cell line SKOV3 and the expression of mismatch repair gene HMLH1/HMSH2, and to investigate the potential mechanism of its antitumorigenesis. Methods Human ovarian cancer cell line SKOV3 was treated with 5-Aza-CdR(0.5, 5 and 50 ?mol/L), a specific demethylation agent for 3 d, and then cultured in RPMI-1640 medium for 7 d.The growth of cells was examined by MTT assay. The apoptosis was analyzed by flow cytometry. The expression of HMLH1 and HMSH2 mRNA was observed by semi-quantitative reverse transcription polymerase chain reaction(RT-PCR). Results SKOV3 cells treated with 5-Aza-CdR displayed a slow growth rate in comparison with that of the control cells, The apoptosis rates of each group were 10.59%?1.57%、17.52%?1.72%、34.10%?1.45%,respectively,which were markedly higher than that of control(P

Research Advance of Muir-Torre Syndrome / 中国普外基础与临床杂志

Objective To review recent studies on Muir Torre syndrome (MTS) and to improve the knowledge about MTS.Methods The literatures in recent years on clinic and gene research of MTS were reviewed.Results MTS was is a rare autosomal dominant disorder characterized by the predisposition to both sebaceous tumors (or multiple keratoacanthomas) and internal malignancies. Gastrointestinal cancers were the most common kind of internal malignancies in MTS patients(61%),followed by genitourinary cancers(22%). In most cases(56%),sebaceous tumors appeared after the emergence of internal maliganancy. Both hereditary nonpolyposis colorectal cancer(HNPCC) and MTS were caused by germline mutations in the DNA mismatch repair genes. MTS patients exhibit significantly more mutations in the hMSH2 than in the hMLH1. In these cases , both internal and skin tumors showed the characteristic of high microsatellite instability(MSI).Conclusion The presence of sebaceous tumors(or multiple keratoacanthomas) necessitates the search for internal malignancies. It is mandatory that patients with MTS, as patients with HNPCC, should be regularly followed up to search new malignancies. Evaluation and monitoring of the family members of patients are also necessary. The patients and their families should be counseled for genetic test. Sequencing the hMSH2 gene should be the prior selection of further examinations when clinical manifestations, history and laboratory tests suggest MTS.