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1.
J Agric Food Chem ; 68(7): 1974-1985, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31971785

RESUMO

Our aim was to investigate DNA mismatch repair (MMR) genes regulating cadmium tolerance in two soybean cultivars. Cultivars Liaodou 10 (LD10, Cd-sensitive) and Shennong 20 (SN20, Cd-tolerant) seedlings were grown hydroponically on Murashige and Skoog (MS) media containing 0-2.5 mg·L-1 Cd for 4 days. Cd stress induced less random amplified polymorphism DNA (RAPD) polymorphism in LD10 than in SN20 roots, causing G1/S arrest in LD10 and G2/M arrest in SN20 roots. Virus-induced gene silencing (VIGS) of MLH1 in LD10-TRV-MLH1 plantlets showed markedly diminished G1/S arrest but enhanced root length/area under Cd stress. However, an increase in G1/S arrest and reduction of G2/M arrest occurred in SN20-TRV-MSH2 and SN20-TRV-MSH6 plantlets with decreased root length/area under Cd stress. Taken together, we conclude that the low expression of MSH2 and MSH6, involved in the G2/M arrest, results in Cd-induced DNA damage recognition bypassing the MMR system to activate G1/S arrest with the assistance of MLH1. This then leads to repressed root growth in LD10, explaining the intervarietal difference in Cd tolerance in soybean.


Assuntos
Cádmio/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Plantas/metabolismo , Soja/genética , Soja/metabolismo , Cádmio/toxicidade , Dano ao DNA/efeitos dos fármacos , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Pontos de Checagem da Fase G2 do Ciclo Celular , Proteínas de Plantas/genética , Soja/efeitos dos fármacos
2.
Cancer Treat Rev ; 84: 101950, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31918022

RESUMO

Recent advances in our understanding of the molecular biology of gastric and oesophageal cancers have shown that gastroesophageal adenocarcinoma should be considered as one disease spectrum. Clinical management of these cancers is challenging, with poor outcomes in both early and late disease settings. Certain molecular subsets of gastroesophageal adenocarcinoma demonstrate features that suggest immunotherapy could be an effective treatment. Immunogenetic markers, including mismatch repair deficiency, PD-L1 status and tumour infiltrating lymphocytes influence overall prognosis. They may also determine the response to adjuvant and neoadjuvant conventional chemotherapy. Initial results from immunotherapy trials for gastroesophageal cancer have however been mixed, with poor overall responses in the first- and second-line settings. This review aims to discuss how better understanding of these immune and genetic interactions may lead to better selection of patients for conventional and immune based therapies, and therefore improve patient outcomes. We also discuss the challenges in implementing this new understanding in routine practice, and the current limitations of immune based treatments for gastroesophageal cancer.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Antígenos de Neoplasias/imunologia , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Quimioterapia Adjuvante , Reparo de Erro de Pareamento de DNA/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/imunologia , Humanos , Fenômenos Imunogenéticos , Linfócitos do Interstício Tumoral/imunologia , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/imunologia , Instabilidade de Microssatélites , Terapia Neoadjuvante , Seleção de Pacientes , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia
3.
Cancer Sci ; 111(3): 1008-1019, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31922331

RESUMO

ARID1A, one of the subunits in SWI/SNF chromatin remodeling complex, is frequently mutated in gastric cancers with microsatellite instability (MSI). The most frequent MSI in solid-type poorly differentiated adenocarcinoma (PDA) has been reported, but the SWI/SNF complex status in solid-type PDA is still largely unknown. We retrospectively analyzed 54 cases of solid-type PDA for the expressions of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), SWI/SNF complex subunits (ARID1A, INI1, BRG1, BRM, BAF155, and BAF170) and EBER, and mutations in KRAS and BRAF. We analyzed 40 cases of another histological type of gastric cancer as a control group. The solid-type PDAs showed coexisting glandular components (76%), MMR deficiency (39%), and complete/partial loss of ARID1A (31%/7%), INI1 (4%/4%), BRG1 (48%/30%), BRM (33%/33%), BAF155 (13%/41%), and BAF170 (6%/2%), EBER positivity (4%), KRAS mutation (2%), and BRAF mutation (2%). Compared to the control group, MMR deficiency and losses of ARID1A, BRG1, BRM, and BAF155 were significantly frequent in solid-type PDAs. Mismatch repair deficiency was associated with the losses of ARID1A, BRG1, and BAF155 in solid-type PDAs. In the MMR-deficient group, solid components showed significantly more frequent losses of ARID1A, BRG1, BRM, and BAF155 compared to glandular components (P = .0268, P = .0181, P = .0224, and P = .0071, respectively). In the MMR-proficient group, solid components showed significantly more frequent loss of BRG1 compared to glandular components (P = .012). In conclusion, solid-type PDAs showed frequent losses of MMR proteins and the SWI/SNF complex. We suggest that loss of the SWI/SNF complex could induce a morphological shift from differentiated-type adenocarcinoma to solid-type PDA.


Assuntos
Adenocarcinoma/genética , Montagem e Desmontagem da Cromatina/genética , Reparo de Erro de Pareamento de DNA/genética , Proteínas de Ligação a DNA/genética , Neoplasias Gástricas/genética , Fatores de Transcrição/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Feminino , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação/genética , Estudos Retrospectivos
4.
Nat Commun ; 11(1): 139, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949146

RESUMO

Mismatch repair deficient (dMMR) gastro-oesophageal adenocarcinomas (GOAs) show better outcomes than their MMR-proficient counterparts and high immunotherapy sensitivity. The hypermutator-phenotype of dMMR tumours theoretically enables high evolvability but their evolution has not been investigated. Here we apply multi-region exome sequencing (MSeq) to four treatment-naive dMMR GOAs. This reveals extreme intratumour heterogeneity (ITH), exceeding ITH in other cancer types >20-fold, but also long phylogenetic trunks which may explain the exquisite immunotherapy sensitivity of dMMR tumours. Subclonal driver mutations are common and parallel evolution occurs in RAS, PIK3CA, SWI/SNF-complex genes and in immune evasion regulators. MSeq data and evolution analysis of single region-data from 64 MSI GOAs show that chromosome 8 gains are early genetic events and that the hypermutator-phenotype remains active during progression. MSeq may be necessary for biomarker development in these heterogeneous cancers. Comparison with other MSeq-analysed tumour types reveals mutation rates and their timing to determine phylogenetic tree morphologies.


Assuntos
Reparo de Erro de Pareamento de DNA , Neoplasias Esofágicas/genética , Heterogeneidade Genética , Neoplasias Gástricas/genética , Adenocarcinoma/genética , Proteínas de Ligação a DNA/genética , Exoma , Genes Neoplásicos/genética , Humanos , Evasão da Resposta Imune , Imunoterapia , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Mutação , Fenótipo , Filogenia
5.
Isr Med Assoc J ; 22(1): 32-36, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31927803

RESUMO

BACKGROUND: Evaluation of mismatch repair (MMR) deficiency is conducted via immunohistochemistry or by microsatellite instability (MSI) analysis. Heterogeneous immunohistochemistry staining for MMR proteins may show different patterns; however, according to current guidelines, all of those patterns should be interpreted as MMR proficient. This conclusion might lead to false negative results because although most cases of heterogeneity stem from technical factors and biological variability, other types of heterogeneity represent true MMR deficiency. OBJECTIVES: To identify a unique heterogeneity pattern that is associated with true MMR loss. METHODS: We analyzed 145 cases of colorectal carcinoma. Immunohistochemistry staining for MLH1, PMS2, MSH2, and MSH6 were performed. We defined geographic heterogeneity as areas of tumor nuclear staining adjacent to areas of loss of tumor nuclear staining with intact staining in the surrounding stroma. All cases were evaluated for the presence of geographic heterogeneity. In addition, 24 cases were also evaluated by MSI testing. RESULTS: Of the 145 cases, 24 (16.5%) were MMR deficient. Of the 24 cases for which MSI analysis was also available, 10 cases (41.7%) demonstrated biological heterogeneity, 5 (20.8%) demonstrated technical heterogeneity, and 2 (8.3%) demonstrated geographic heterogeneity. Only the two cases with geographic heterogeneity were MSI-high via MSI analysis. In addition, a germline mutation in MSH-6 was identified in one of these cases. CONCLUSIONS: Geographic heterogeneity may raise a suspicion for a MMR-deficient case, which should be further analyzed using additional methodologies such as MSI analysis.


Assuntos
Reparo de Erro de Pareamento de DNA/genética , Proteínas MutS/genética , Adenoma/genética , Adenoma/patologia , Adulto , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Corantes , Heterogeneidade Genética , Humanos , Masculino
7.
Gynecol Oncol ; 156(1): 194-202, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31757464

RESUMO

OBJECTIVES: Assess outcomes of a clinical cohort of patients with endometrioid endometrial cancer (EEC) harboring somatic POLE exonuclease domain mutations (EDMs). METHODS: Patients were consented to a protocol of tumor-normal massively parallel sequencing of 410-468 cancer related genes. EECs subjected to sequencing from 2014 to 2018 were reviewed. Tumors with somatic POLE EDMs were identified. EECs were assessed for microsatellite instability (MSI) using MSIsensor and immunohistochemical analysis for mismatch repair (MMR) proteins. RESULTS: Of the 451 EECs sequenced, 23 had a POLE EDM (5%): 20 primary and 3 recurrent tumors sequenced. Nineteen cases (83%) were stage I/II and 4 (17%) were stages III/IV. Thirteen EECs (57%) were of FIGO grades 1/2, 10 (43%) grade 3. All patients were treated with surgery and 17 (89%) received adjuvant therapy. Five (22%) demonstrated loss of DNA MMR protein expression, none were due to Lynch syndrome. MSIsensor scores were conclusive for 21 samples: 19 were microsatellite stable and 2 MSI-high. After median follow-up of 30 months, 4/23 (17%) developed recurrences: 3 with initial grade 3 stage I and 1 with grade 1 stage III disease. One patient with grade 2 stage IV EEC had progressive disease after treatment. CONCLUSIONS: Patients with POLE EDM EEC have been shown to have a favorable prognosis. In this real-world cohort of patients, de novo metastatic disease and recurrences in initially uterine-confined cases were observed. Further research is warranted before incorporating the presence of POLE EDM into decision-making regarding adjuvant therapy.


Assuntos
Carcinoma Endometrioide/genética , DNA Polimerase II/genética , Neoplasias do Endométrio/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , Adulto , Idoso , Carcinoma Endometrioide/enzimologia , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/terapia , Estudos de Coortes , Reparo de Erro de Pareamento de DNA , DNA Polimerase II/metabolismo , Neoplasias do Endométrio/enzimologia , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/terapia , Feminino , Humanos , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Prognóstico , Estudos Prospectivos
8.
Cancer Treat Rev ; 82: 101935, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31821983

RESUMO

Temozolomide is an oral alkylating agent used for treating several cancers including glioblastoma and melanoma. Promising, albeit limited, activity and efficacy of temozolomide have been reported in pretreated patients with metastatic colorectal cancer bearing MGMT promoter methylation. MGMT silencing and proficiency of the mismatch repair system were considered the major predictive biomarkers of sensitivity to temozolomide. Refinement of established biomarkers and integration with those related to alteration in specific DNA-damage response pathways such as base excision repair are promising strategies for selecting metastatic colorectal patients to this old drug with several potential novel applications. Then, mounting preclinical and clinical observations have linked acquired resistance to temozolomide to emergence of alterations in the mismatch repair system. Whilst accounting for tumor cells capability of escaping apoptosis when exposed to temozolomide, inactivation of key mismatch-repair proteins will ultimately lead to increasing tumor mutational burden. This drug-induced mismatch deficient-like phenotype is being exploited in proof-of-concept trials combining temozolomide and immune checkpoint inhibitors in metastatic colorectal cancer.


Assuntos
Neoplasias Colorretais , Temozolomida/farmacologia , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Humanos , Metástase Neoplásica , Estadiamento de Neoplasias , Proteínas Supressoras de Tumor/genética
9.
Anticancer Res ; 39(12): 6431-6441, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810907

RESUMO

BACKGROUND/AIM: About 15-20% of colorectal cancers (CRCs) have deficiency in a mismatch repair (MMR) protein. MMR has a high level of microsatellite instability (MSI-H). We have conducted this review and meta-analysis to determine the prognostic role of MSI-H status in stage II CRC. MATERIALS AND METHODS: We searched PubMed, EMBASE, The Cochrane Library, Web of Science, and SCOPUS for studies reporting data on overall survival (OS) and disease-free or relapse-free survival (DFS or RFS) for MSI-H compared to microsatellite stable (MSS) CRC. RESULTS: A total of 39 studies were analysed, including 12,110 patients. MSI-H status was associated with a significantly reduced risk of death (HR=0.64, 95%CI=0.52-0.8, p<0.01) and relapse (HR=0.59, 95%CI=0.45-0.77, p<0.01) in stage II CRC. CONCLUSION: MSI-H represents an important prognostic determinant in stage II CRC and may be considered when estimating the risk of recurrence in stage II CRC.


Assuntos
Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Instabilidade de Microssatélites , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , Humanos , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida
10.
Anticancer Res ; 39(12): 6547-6553, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810920

RESUMO

AIM: To evaluate the frequency of loss of mediator of DNA damage checkpoint protein 1 (MDC1) protein expression in endometrial cancer (EC) and to determine whether loss of MDC1 is associated with certain clinicopathological parameters. MATERIALS AND METHODS: MDC1 expression was examined in 426 samples of EC. The nuclear immunoreactivity of the protein was defined as: negative, weak, moderate and strong. RESULTS: Loss of MDC1 expression (defined as negative nuclear staining) was found in 8.9% (38/426) of ECs and was significantly associated with the loss of MRE11 homolog, double-strand break repair nuclease, RAD50 double-strand break repair protein and nibrin complex components. In addition, loss of expression of MDC1 showed a significant correlation with any mismatch repair deficiency, with endometrioid histological subtype and low tumour grading. CONCLUSION: Based on these findings, we suggest that MDC1 loss frequently occurs in ECs with microsatellite instability. Due to deficient homologous recombination DNA repair, MDC1-negative ECs might show an increased sensitivity to poly(ADP-ribose) polymerase-inhibitory therapy.


Assuntos
Proteínas de Ciclo Celular/deficiência , Enzimas Reparadoras do DNA/deficiência , Proteínas de Ligação a DNA/deficiência , Neoplasias do Endométrio/metabolismo , Proteína Homóloga a MRE11/deficiência , Proteínas Nucleares/deficiência , Proteínas Nucleares/metabolismo , Transativadores/metabolismo , Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio/patologia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Instabilidade de Microssatélites , Estadiamento de Neoplasias , Análise de Sobrevida , Análise Serial de Tecidos
11.
Anticancer Res ; 39(12): 6731-6741, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810938

RESUMO

BACKGROUND/AIM: Histone deacetylase 6 (HDAC6) is considered as one of the most promising targets in drug development for cancer therapy. Drug resistance is a major cause of treatment failure in many cancers including glioblastoma (GBM), the most lethal malignant tumor. The role of HDAC6 in GBM resistance and its underlying mechanisms have not been well elucidated. Herein, we investigated the function of HDAC6 in modulating GBM resistance. MATERIALS AND METHODS: The anticancer effects of four structurally distinct selective HDAC6 inhibitors were addressed using western blot, flow cytometry, CCK-8 assay, and CI in temozolomide (TMZ)-resistant GBM cells. RESULTS: We showed that HDAC6-selecitve inhibitors block activation of the EGFR and p53 pathways in TMZ-resistant GBM cells. Importantly, the inhibition of HDAC6 correlates with increased levels of MSH2 and MSH6, key DNA mismatch repair proteins, in TMZ-resistant GBM cells. In addition to the MSH, HDAC6 inhibitors decrease MGMT expression in TMZ-resistant GBM cells. Furthermore, HDAC6 inhibitors increase TMZ sensitivity and efficiently induce apoptosis in TMZ-resistant GBM cells. CONCLUSION: Selective inhibition of HDAC6 may be a promising strategy for the treatment of TMZ-resistant GBM.


Assuntos
Neoplasias Encefálicas/enzimologia , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/enzimologia , Desacetilase 6 de Histona/antagonistas & inibidores , Proteína 2 Homóloga a MutS/metabolismo , Antineoplásicos Alquilantes/uso terapêutico , Derivados de Benzeno/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular , Reparo de Erro de Pareamento de DNA/fisiologia , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Receptores ErbB/metabolismo , Glioblastoma/tratamento farmacológico , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Pirimidinas/farmacologia , Temozolomida/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima
12.
Medicine (Baltimore) ; 98(51): e18279, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31860975

RESUMO

RATIONALE: Lynch syndrome (LS) is an autosomal dominant cancer predisposition condition caused by germline heterozygous mutations in mismatch repair (MMR) genes. However, as one of the MMR genes, PMS2 mutation-induced LS-associated endometrial cancer (LSAEC) was rarely reported. PATIENT CONCERNS: A 26-year-old female patient suffered from prolonged menstrual period and increased menstrual flow for 2 months. DIAGNOSES: The patient was diagnosed with cervix CIN III, endometrial cancer (EC), anemia, and LS. INTERVENTIONS: Total hysterectomy, bilateral salpingectomy, pelvic lymphadenectomy were performed for treating EC, while ovariectomy was refused by the patient. The patient underwent postoperative chemotherapy with paclitaxel combined with carboplatin for 6 courses of treatment. Laparoscopic partial enterectomy was applied for treating colon cancer 5 years later after the surgery treatment for EC. Besides, Sanger sequencing and high-throughput genome sequencing were employed to detect the genetic status of the family that included two generations with four members. Immunohistochemistry (IHC) staining was used to identify the function of PMS2 mutation. OUTCOMES: The 26-year-old Chinese patient suffered from LSAEC and recovered well after surgery. A PMS2 germline heterozygous mutation (c.1577delA) was confirmed by gene sequencing 5 years later. In addition, PMS2 mutation was verified by IHC. The patient was followed up for 7 years. LESSONS: Carrying PMS2 germline mutation (c.1577delA) confers an extremely high susceptibility of suffering from LS-associated cancers. Thus, close clinical monitoring and prophylactic surgery are highly recommended to reduce the morbidity and mortality of LS-associated cancers.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias do Endométrio/genética , Mutação em Linhagem Germinativa/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Adulto , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Neoplasias do Endométrio/etiologia , Neoplasias do Endométrio/patologia , Endométrio/patologia , Feminino , Humanos
13.
Z Gastroenterol ; 57(11): 1309-1320, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31739377

RESUMO

INTRODUCTION: Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome and accounts for ~3 % of all CRCs. This autosomal dominant disorder is caused by germline mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM). One in 300 individuals of the general population are considered to be mutation carriers (300 000 individuals/Germany). Mutation carriers are at a high CRC risk of 15-46 % till the age of 75 years. LS also includes a variety of extracolonic malignancies such as endometrial, small bowel, gastric, urothelial, and other cancers. METHODS: The German Consortium for Familial Intestinal Cancer consists of 14 university centers in Germany. The aim of the consortium is to develop and evaluate surveillance programs and to further translate the results in clinical care. We have revisited and updated the clinical management guidelines for LS patients in Germany. RESULTS: A surveillance colonoscopy should be performed every 12-24 months starting at the age of 25 years. At diagnosis of first colorectal cancer, an oncological resection is advised, an extended resection (colectomy with ileorectal anastomosis) has to be discussed with the patient. The lifetime risk for gastric cancer is 0.2-13 %. Gastric cancers detected during surveillance have a lower tumor stage compared to symptom-driven detection. The lifetime risk for small bowel cancer is 4-8 %. About half of small bowel cancer is located in the duodenum and occurs before the age of 35 years in 10 % of all cases. Accordingly, patients are advised to undergo an esophagogastroduodenoscopy every 12-36 months starting by the age of 25 years. CONCLUSION: LS colonic and extracolonic clinical management, surveillance and therapy are complex and several aspects remain unclear. In the future, surveillance and clinical management need to be more tailored to gene and gender. Future prospective trials are needed.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/patologia , Reparo de Erro de Pareamento de DNA , Endoscopia do Sistema Digestório/métodos , Guias de Prática Clínica como Assunto , Comportamento de Redução do Risco , Neoplasias Colorretais , Neoplasias Colorretais Hereditárias sem Polipose/genética , Alemanha , Humanos , Vigilância da População , Fatores de Tempo
14.
BMC Cancer ; 19(1): 971, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31638937

RESUMO

BACKGROUND: Microsatellite instability (MSI), resulting from a defective mismatch repair system, occurs in approximately 15% of sporadic colorectal cancers (CRC). Since MSI is associated with a poor response to 5-fluorouracile based chemotherapy and is a positive predictive marker of immunotherapy, it is routine practice to evaluate the MSI status of resected tumors in CRC patients. MSIsensor is a novel computational tool for determining MSI status using Next Generation Sequencing. However, it is not widely used in the clinic and has not been independently validated in exome data from CRC. To facilitate clinical implementation of computational determination of MSI status, we compared MSIsensor to current gold standard methods for MSI testing. METHODS: MSI status was determined for 130 CRC patients (UICC stage I-IV) using immunohistochemistry, PCR based microsatellite stability testing and by applying MSIsensor to exome sequenced tumors and paired germline DNA. Furthermore, we investigated correlation between MSI status, mutational load and mutational signatures. RESULTS: Eighteen out of 130 (13.8%) patients were microsatellite instable. We found a 100% agreement between MSIsensor and gold standard methods for MSI testing. All MSI tumors were hypermutated. In addition, two microsatellite stable (MSS) tumors were hypermutated, which was explained by a dominant POLE signature and pathogenic POLE mutations (p.Pro286Arg and p.Ser459Phe). CONCLUSION: MSIsensor is a robust tool, which can be used to determine MSI status of tumor samples from exome sequenced CRC patients.


Assuntos
Neoplasias Colorretais/genética , Biologia Computacional/métodos , Exoma/genética , Instabilidade de Microssatélites , Repetições de Microssatélites/genética , Sequenciamento Completo do Exoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Neoplasias Colorretais/tratamento farmacológico , Reparo de Erro de Pareamento de DNA/genética , Feminino , Fluoruracila/uso terapêutico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Imunoterapia , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase , Prognóstico
15.
Anticancer Res ; 39(10): 5505-5513, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570444

RESUMO

BACKGROUND/AIM: The potential of the DNA mismatch repair (MMR) system as a prognostic predictor has been evaluated in several cancer types. However, associations between MMR and the prognostic factors of ovarian cancer are poorly understood. PATIENTS AND METHODS: MLH1 expression was evaluated by immunohistochemistry in patients with advanced serous ovarian cancer treated with platinum- and taxane-based chemotherapy. Associations between MLH1 expression and clinicopathological factors as well as claudin-4 expression were examined. RESULTS: Low MLH1 expression was significantly associated with increased progression-free and overall survival, and a normalisation of CA125 levels after chemotherapy. Additionally, low claudin-4 expression was more frequently found among the group with low MLH1 expression. CONCLUSION: Low MLH1 expression was associated with improved prognosis and is a possible predictor of the chemosensitivity of ovarian cancer. Claudin-4 might be involved in the molecular mechanisms underlying how MLH1 influences survival and chemosensitivity in patients with ovarian cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Proteína 1 Homóloga a MutL/metabolismo , Compostos Organoplatínicos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Taxoides/farmacologia , Idoso , Antígeno Ca-125/metabolismo , Claudina-4/metabolismo , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Feminino , Humanos , Imuno-Histoquímica/métodos , Neoplasias Ovarianas/patologia , Prognóstico , Intervalo Livre de Progressão
16.
Zhonghua Zhong Liu Za Zhi ; 41(10): 734-741, 2019 Oct 23.
Artigo em Chinês | MEDLINE | ID: mdl-31648494

RESUMO

Microsatellite instability (MSI) which resulted from the deficiency of DNA mismatch repair (MMR), is an important clinical significance in the related solid tumors, such as colorectal cancer and endometrial cancer. There are several methods to detect MSI status, including immunohistochemistry for MMR protein, multiplex fluorescent polymerase chain reaction (PCR) for microsatellite site and MSI algorithm based on next generation sequencing (NGS). The consensus elaborates the definition and clinical significance of MSI as well as the advantages and disadvantages of the three detection methods. Through this expert consensus, we hope to promote the screening which based on MSI status in malignant tumors and improve the acknowledge of clinicians about various testing methods. Thereby, they could interpret the results more accurately and provide better clinical services to patients.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Colorretais/genética , Consenso , Assistência à Saúde/normas , Instabilidade de Microssatélites , Guias de Prática Clínica como Assunto , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , China , Neoplasias Colorretais/patologia , Reparo de Erro de Pareamento de DNA , Sequência de DNA Instável , Neoplasias do Endométrio , Feminino , Humanos , Imuno-Histoquímica , Repetições de Microssatélites , Microscopia de Fluorescência , Reação em Cadeia da Polimerase
17.
Indian J Cancer ; 56(4): 309-314, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31607698

RESUMO

CONTEXT: The incidence of colorectal cancers (CRCs) in young Indian patients is higher than the international average. CRCs in young patients are commonly of mucinous type and show microsatellite instability (MSI). AIMS: To ascertain the MSI status of mucinous CRCs in patients ≤40 years of age by molecular testing and to correlate this with immunohistochemical (IHC) analysis and tumor histology. SUBJECTS AND METHODS: Archived formalin-fixed paraffin embedded tissue blocks of 30 young mucinous CRC patients were retrieved. MSI testing was done using two mononucleotide markers - BAT26 and NR24. IHC analysis was done using MLH1, MSH2, and MSH6. Histological features of all cases were studied. Data were analyzed using the SPSS software and the Pearson's chi-square test and Fisher's exact test. RESULTS: Eight out of 30 cases (26.7%) showed MSI by molecular testing. IHC identified seven of these cases. Histological features showing a statistically significant association with MSI were the presence of a well-differentiated adenocarcinoma component (P = 0.003), peritumoral lymphocytes (P = 0.002) and tumor budding (P = 0.021). CONCLUSION: The detection of defective mismatch repair (MMR) proteins using IHC for MLH1, MSH2, and MSH6 and molecular testing using BAT26 and NR24 appears to be a good protocol to detect CRCs with MSI. Histology could be useful in identifying cases that require screening for presence of MMR protein defects.


Assuntos
Adenocarcinoma Mucinoso/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Marcadores Genéticos/genética , Repetições de Microssatélites/genética , Adenocarcinoma Mucinoso/diagnóstico , Adenocarcinoma Mucinoso/patologia , Adulto , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Reparo de Erro de Pareamento de DNA , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Instabilidade de Microssatélites , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Patologia Molecular , Adulto Jovem
18.
J Cancer Res Clin Oncol ; 145(12): 2891-2899, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31617076

RESUMO

PURPOSE: Microsatellites are widely distributed repetitive DNA motifs, accounting for approximately 3% of the genome. Due to mismatch repair system deficiency, insertion or deletion of repetitive units often occurs, leading to microsatellite instability. In this review, we aimed to explore the relationship between MSI and biological behaviour of colorectal carcinoma, gastric carcinoma, lymphoma/leukaemia and endometrial carcinoma, as well as the application of frameshift peptide vaccines in cancer therapy. METHODS: The relevant literature from PubMed and Baidu Xueshu were reviewed in this article. The ClinicalTrials.gov database was searched for clinical trials related to the specific topic. RESULTS: Microsatellite instability is divided into three subtypes: high-level, low-level microsatellite instability, and stable microsatellites. The majority of tumour patients with high-level microsatellite instability often show a better efficacy and prognosis than those with low-level microsatellite instability or stable microsatellites. In coding regions, especially for genes involved in tumourigenesis, microsatellite instability often results in inactivation of proteins and contributes to tumourigenesis. Moreover, the occurrence of microsatellite instability in coding regions can also cause the generation of frameshift peptides that are thought to be unknown and novel to the individual immune system. Thus, these frameshift peptides have the potential to be biomarkers to raise tumour-specific immune responses. CONCLUSION: MSI has the potential to become a key predictor for evaluating the degree of malignancy, efficacy and prognosis of tumours. Clinically, MSI patterns will provide more valuable information for clinicians to create optimal individualized treatment strategies based on frameshift peptides vaccines.


Assuntos
Mutação da Fase de Leitura/genética , Repetições de Microssatélites/genética , Neoplasias/genética , Animais , Carcinogênese/genética , Ensaios Clínicos como Assunto , Reparo de Erro de Pareamento de DNA/genética , Humanos , Instabilidade de Microssatélites , Prognóstico
19.
Turk Neurosurg ; 29(5): 778-784, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31529454

RESUMO

AIM: To evaluate the frequency and prognostic significance of microsatellite instability (MSI) in patients with glioblastoma (GBM), an immunohistochemical analysis of mismatch repair (MMR) proteins was performed. MATERIAL AND METHODS: A total of 71 patients with GBM who underwent surgery between 2011 and 2019, were included in the study. MMR protein expression was examined using immunohistochemistical analysis of tumor tissue samples; the association between the MMR status and clinicopathological findings was evaluated. RESULTS: Immunohistochemical analysis revealed expressions of MLH1, MSH2, MSH6, and PMS2 proteins in 67 (94.4%), 65 (91.5%), 67 (94.4%), and 64 (90.1%) patients, respectively. Among the 71 patients, 64 (90.1%) expressing all MMR proteins were considered microsatellite stable (MSS), and 7 (9.9%) patients showing loss of at least one of the MMR proteins were considered to show MSI. Tumor recurrence was noted in 25 (39.1%) patients in the MSS GBM group, and 4 (57.1%) patients in the MSI GBM group (p=0.433). The overall median survival was 30.65 ± 5.1 and 10.71 ± 5.2 months in the MSS GBM and MSI GBM groups, respectively (p=0.059). CONCLUSION: The results of this study showed no significant relationships between MMR protein expression and recurrence rates or overall survival in patients with GBM.


Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , Instabilidade de Microssatélites , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Reparo de Erro de Pareamento de DNA/genética , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
20.
Presse Med ; 48(9): 904-914, 2019 Sep.
Artigo em Francês | MEDLINE | ID: mdl-31561847

RESUMO

About 5% of colorectal cancer (CRC) cases occurred in the context of an underlying hereditary predisposition syndrome. Lynch syndrome is the main causes of hereditary CRC but is also associated with a higher risk of other cancers (such as endometrial cancer and ovarian cancer). It is the consequence of constitutional mutation in a MisMatch Repair (MMR) gene, involved in DNA repair: MLH1, MSH2, MSH6 or PMS2; or of the EPCAM gene (MSH2 promotor). If a mutation predisposing to Lynch Syndrome is identified in an individual, special monitoring should be initiated, adapted to estimated cancer risk. Clinical criteria (Amsterdam II and Bethesda) have been validated to identify the patients who should be referred for genetic counseling in order to initiate constitutional DNA testing. Furthermore, the French National Cancer Institute (INCa) systematically recommend tumoral testing looking for MMR system failure in case of CRC diagnosed under 60, endometrial cancer diagnosed under 50 or whatever the age in patients diagnosed with CRC or endometrial cancer harbouring personal or familal history of Lunch Syndrome cancers. In this review, we will discuss how to detect Lynch syndrome (identification of the index case and family screening) and how to monitor it in 2019.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Fatores Etários , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Detecção Precoce de Câncer , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Intestino Grosso , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Linhagem , Vigilância da População/métodos , Guias de Prática Clínica como Assunto , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Urológicas/diagnóstico , Neoplasias Urológicas/genética
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