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 gr...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-展开更多
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 pr...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.展开更多
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 investigat...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.展开更多
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: Relevan...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.展开更多
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...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.展开更多
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...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.展开更多
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 a...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.展开更多
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...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.展开更多
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 sp...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. .展开更多
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 mic...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.展开更多
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 ge...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.展开更多
文摘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-
文摘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.
文摘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.
文摘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.
基金Supported by a grant from Chinese Scientific Academy Creative Foundation (No. DICPkaaaabc).
文摘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.
文摘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.
基金Project supported by the National Natural Science Foundation of China
文摘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.
文摘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.
文摘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. .
基金Supported by FEDER through Programa Operacional Facto-res de Competitividade-COMPETENational Funds,No.FCOMP-01-0124-FEDER-000022Grants from Fundacao para a Ciência e a Tecnologia(FCT),No.IF/00136/2013(to Velho S),No.SFRH/BPD/63716/2009(to Fernandes MS)and No.SFRH/BPD/33420/2008(to Leite M)
文摘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.
基金This work was supported by the National Natural Science Foundation of China(Grant Nos.82072588,82002601,81872143,and 81702280)the National Science and Technology Support Program of China(Grant Nos.2015BAI12B15 and 2018ZX09201015)+2 种基金the National Key Research and Development Program of Chinathe Net Construction of Human Genetic Resource Bio-bank in North China(2016YFC1201703),the Projects of Science and Technology of Tianjin(Grant Nos.13ZCZCSY20300 and 18JCQNJC82700)the Key Project of Tianjin Health and Family Planning Commission(Grant No.16KG126).
文摘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.