RESUMEN
The calcitonin gene-related peptide (CGRP) is implicated in the pathogenesis of several pain-related syndromes, including migraine. Targeting CGRP and its receptor by their antagonists and antibodies was a breakthrough in migraine therapy, but the need to improve efficacy and limit the side effects of these drugs justify further studies on the regulation of CGRP in migraine. The expression of the CGRP encoding gene, CALCA, is modulated by epigenetic modifications, including the DNA methylation, histone modification, and effects of micro RNAs (miRNAs), circular RNAs, and long-coding RNAs (lncRNAs). On the other hand, CGRP can change the epigenetic profile of neuronal and glial cells. The promoter of the CALCA gene has two CpG islands that may be specifically methylated in migraine patients. DNA methylation and lncRNAs were shown to play a role in the cell-specific alternative splicing of the CALCA primary transcript. CGRP may be involved in changes in neural cytoarchitecture that are controlled by histone deacetylase 6 (HDAC6) and can be related to migraine. Inhibition of HDAC6 results in reduced cortical-spreading depression and a blockade of the CGRP receptor. CGRP levels are associated with the expression of several miRNAs in plasma, making them useful peripheral markers of migraine. The fundamental role of CGRP in inflammatory pain transmission may be epigenetically regulated. In conclusion, epigenetic connections of CGRP should be further explored for efficient and safe antimigraine therapy.
Asunto(s)
MicroARNs , Trastornos Migrañosos , ARN Largo no Codificante , Péptido Relacionado con Gen de Calcitonina/metabolismo , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Epigénesis Genética , Humanos , MicroARNs/genética , MicroARNs/uso terapéutico , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/genética , Trastornos Migrañosos/metabolismo , Dolor/tratamiento farmacológico , ARN Largo no Codificante/uso terapéuticoRESUMEN
Replication timing (RT) is a cellular program to coordinate initiation of DNA replication in all origins within the genome. RIF1 (replication timing regulatory factor 1) is a master regulator of RT in human cells. This role of RIF1 is associated with binding G4-quadruplexes and changes in 3D chromatin that may suppress origin activation over a long distance. Many effects of RIF1 in fork reactivation and DNA double-strand (DSB) repair (DSBR) are underlined by its interaction with TP53BP1 (tumor protein p53 binding protein). In G1, RIF1 acts antagonistically to BRCA1 (BRCA1 DNA repair associated), suppressing end resection and homologous recombination repair (HRR) and promoting non-homologous end joining (NHEJ), contributing to DSBR pathway choice. RIF1 is an important element of intra-S-checkpoints to recover damaged replication fork with the involvement of HRR. High-resolution microscopic studies show that RIF1 cooperates with TP53BP1 to preserve 3D structure and epigenetic markers of genomic loci disrupted by DSBs. Apart from TP53BP1, RIF1 interact with many other proteins, including proteins involved in DNA damage response, cell cycle regulation, and chromatin remodeling. As impaired RT, DSBR and fork reactivation are associated with genomic instability, a hallmark of malignant transformation, RIF1 has a diagnostic, prognostic, and therapeutic potential in cancer. Further studies may reveal other aspects of common regulation of RT, DSBR, and fork reactivation by RIF1.
Asunto(s)
Reparación del ADN/fisiología , Momento de Replicación del ADN/fisiología , Proteínas de Unión a Telómeros/metabolismo , Proteína BRCA1/metabolismo , Cromatina/metabolismo , ADN/metabolismo , Roturas del ADN de Doble Cadena/efectos de los fármacos , Reparación del ADN por Unión de Extremidades/genética , Reparación del ADN por Unión de Extremidades/fisiología , Replicación del ADN/genética , Replicación del ADN/fisiología , Momento de Replicación del ADN/genética , Inestabilidad Genómica/genética , Humanos , Reparación del ADN por Recombinación , Proteínas de Unión a Telómeros/genética , Proteínas de Unión a Telómeros/fisiología , Proteína 1 de Unión al Supresor Tumoral P53/metabolismoRESUMEN
Aging induces several stress response pathways to counterbalance detrimental changes associated with this process. These pathways include nutrient signaling, proteostasis, mitochondrial quality control and DNA damage response. At the cellular level, these pathways are controlled by evolutionarily conserved signaling molecules, such as 5'AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), insulin/insulin-like growth factor 1 (IGF-1) and sirtuins, including SIRT1. Peroxisome proliferation-activated receptor coactivator 1 alpha (PGC-1α), encoded by the PPARGC1A gene, playing an important role in antioxidant defense and mitochondrial biogenesis, may interact with these molecules influencing lifespan and general fitness. Perturbation in the aging stress response may lead to aging-related disorders, including age-related macular degeneration (AMD), the main reason for vision loss in the elderly. This is supported by studies showing an important role of disturbances in mitochondrial metabolism, DDR and autophagy in AMD pathogenesis. In addition, disturbed expression of PGC-1α was shown to associate with AMD. Therefore, the aging stress response may be critical for AMD pathogenesis, and further studies are needed to precisely determine mechanisms underlying its role in AMD. These studies can include research on retinal cells produced from pluripotent stem cells obtained from AMD donors with the mutations, either native or engineered, in the critical genes for the aging stress response, including AMPK, IGF1, MTOR, SIRT1 and PPARGC1A.
Asunto(s)
Envejecimiento , Degeneración Macular/etiología , Daño del ADN , Humanos , Degeneración Macular/metabolismo , Degeneración Macular/fisiopatología , Mitocondrias/metabolismo , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Transducción de SeñalRESUMEN
Endometrial hyperplasia (EH) is a pathological condition characterised by hyperplastic changes in endometrial glandular and stromal structures lining the uterine cavity. Endometrial hyperplasia, particularly with atypia, is a significant clinical concern because it can be a precursor of endometrial cancer. Accurate diagnosis of precancerous lesions of the endometrium and exclusion of coexisting endometrial carcinomas are absolutely required for the optimal management of patients. The classification of endometrial hyperplasia has had numerous terminology. According to the classification of WHO94, based on glandular complexity and nuclear atypia, EH is divided into four groups: non-atypical endometrial hyperplasia (simple, complex) and atypical endometrial hyperplasia (simple, complex). Estimated risk of progression of atypical hyperplasia to endometrial cancer is 8-29%. The American College of Obstetricians and Gynaecologists and the Society of Gynaecological Oncology states that endometrial intraepithelial neoplasia (EIN) classification is superior to the World Health Organisation (WHO 94) classification for histology of endometrial hyperplasia. However, the WHO classification system remains the most commonly used and reported in existing literature. The new classification, WHO 2014, accepted by the International Society of Gynaecological Pathologists, divided hyperplasia into two groups: benign hyperplasia and atypical hyperplasia/endometrial intraepithelial neoplasia (EIN). The WHO 2014 schema is more likely to successfully identify precancerous lesions than the WHO94 classification.
RESUMEN
OBJECTIVE: The main goal of our study was to identify the earliest and specific genetic changes which could be associated with an increased risk of neoplastic transformation in a group of patients with endometrial hyperplasia. Another goal was to characterize genetic changes associated with advanced forms of cancer. MATERIAL AND METHODS: The study involved forty-four (44) female patients, including five (5) patients with no histopathologically confirmed hyperplastic features, twenty-six (26) patients with histopathologically confirmed endometrial hyperplasia, and thirteen (13) patients with diagnosed carcinoma of the endometrium. The study was conducted using a custom-made 4x180 K microarray of BlueGnome. RESULTS: Copy number variations (CNV) were found in the cases without endometrial hyperplasia. Such changes occur with varying frequency in the genome of healthy female population. Significant genome imbalance was identified in the twenty-six (26) (100%) patients with diagnosed hyperplasia and in eleven (11) subjects (84.6%) with diagnosed endometrial cancer. Other not yet reported, changes localized in characteristic regions of the genome were also found.
Asunto(s)
Carcinoma/genética , Carcinoma/patología , Variaciones en el Número de Copia de ADN , Hiperplasia Endometrial/genética , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Adulto , Hiperplasia Endometrial/patología , Femenino , Genómica , Humanos , Persona de Mediana EdadRESUMEN
Group I metabotropic glutamate receptors (mGluRs) are involved in memory formation. The Ca2+ signal derived from stimulation of IP3 receptors (IP3Rs) via mGluRs, initiates protein synthesis that is required for memory consolidation and reconsolidation. However it has been suggested that different mechanisms are triggered by mGluR1/5 activation in these two processes. It is also not clear whether the transient amnesia observed after blockade of group I mGluRs after a reminder, results from disturbance of memory reconsolidation or temporal impairment of recall. The aim of this study was to examine more closely the role of mGluR1 in memory consolidation and reconsolidation and to detect differences in the participation of mGluR1 and mGluR5 in memory retrieval after initial training and after the remainder of the task. Our results demonstrate, that in chicks performing a one-trial passive avoidance task, antagonists of mGluR1, mGluR5 and IP3R significantly disturb memory consolidation and reconsolidation. Inhibition of mGluR5 and IP3R also impairs memory recall, whereas mGluR1 do not seem to participate in this process. The presented data suggest that activation of mGluR1 and mGluR5 is necessary for the correct course of memory consolidation and reconsolidation, whereas mGluR5 are additionally involved in retrieval processes dependent on Ca2+ release from IP3 activated intracellular stores.
Asunto(s)
Reacción de Prevención/fisiología , Memoria/fisiología , Receptores de Glutamato Metabotrópico/metabolismo , Animales , Animales Recién Nacidos , Reacción de Prevención/efectos de los fármacos , Benzoatos/farmacología , Compuestos de Boro/farmacología , Pollos , Glicina/análogos & derivados , Glicina/farmacología , Masculino , Memoria/efectos de los fármacos , Piridinas/farmacología , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/antagonistas & inhibidoresRESUMEN
The cellular reaction to the DNA-damaging agents may modulate individual's cancer susceptibility. This reaction is mainly determined by the efficacy of DNA repair, which in turn, may be influenced by the variability of DNA repair genes, expressed by their polymorphism. The hOGG1 gene encodes a glycosylase of base excision repair and RAD51 specifies a key protein in homologues recombination repair. Both proteins can be involved in the repair of DNA lesions, which are known to contribute to endometrial cancer. In the present work we determined the extent of basal DNA damage and the efficacy of removal of DNA damage induced by hydrogen peroxide and N-methyl-N'-nitro N-nitrosoguanidyne (MNNG) in peripheral blood lymphocytes of 30 endometrial cancer patients and 30 individuals without cancer. The results from DNA damage and repair study were correlated with the genotypes of two common polymorphisms of the hOGG1 and RAD51 genes: a G>C transversion at 1245 position of the hOGG1 gene producing a Ser â Cys substitution at the codon 326 (the Ser326Cys polymorphism) and a G>C substitution at 135 position of the RAD51 gene (the 135G>C polymorphism). DNA damage and repair were evaluated by alkaline single cell gel electrophoresis and genotypes were determined by restriction fragment length polymorphism PCR. We observed a strong association between endometrial cancer and the C/C genotype of the 135G>C polymorphism of the RAD51 gene. Moreover, there was a strong correlation between that genotype and endometrial cancer occurrence in subjects with a high level of basal DNA damage. We did not observe any correlation between the Ser326Cys polymorphism of the hOGG1 gene and endometrial cancer. Our result suggest that the 135G>C polymorphism of the RAD51 gene may be linked to endometrial cancer and can be considered as an additional marker of this disease.
Asunto(s)
Daño del ADN , ADN Glicosilasas/genética , Reparación del ADN , Recombinasa Rad51/genética , Anciano , Alelos , Ensayo Cometa , Neoplasias Endometriales/metabolismo , Femenino , Marcadores Genéticos , Genotipo , Humanos , Persona de Mediana Edad , Polimorfismo Genético , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
AIM: Metabolic activation of estrogens may play a role in endometrial carcinogenesis; and polymorphism of the genes (whose product is involved in this process) may be associated with the modulation of the risk of endometrial cancer. CYP1B1 plays a major role in the metabolism of estrogens, which must firstly bind their receptors, estrogen receptor alpha (ERalpha) or ER beta. In the present study we investigated the association of two polymorphisms of the CYP1B1 gene (Arg48Gly [142C > G] and Leu432Val [4326C > G]) and a polymorphism of the ERalpha gene (975C > G) as well as a combination between them with endometrial cancer occurrence. METHODS: Genotypes were determined in DNA from peripheral blood lymphocytes of 100 endometrial cancer patients and 100 age- and ethnically-matched cancer-free controls by restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR). RESULTS: We found an association between endometrial cancer occurrence and the Arg48Arg (142C > C)-CYP1B1 variant (odds ratio [OR] 2.10; 95% confidence interval [CI] 1.17-3.79) and the 975C > G -ERalpha gene polymorphism (OR 3.84; 95%CI 2.08-7.10). Gene-gene interaction between the Arg48Arg (142C > C) and Leu432Val (4326C > G) variants and between Arg48Gly (142C > G) -CYP1B1 and 975C > G -ERalpha as well as Gly48Gly (142G > G)-CYP1B1 and 975C > G-ERalpha increased the risk of endometrial cancer (OR 2.70; 95%CI 1.12-6.49; OR 2.52; 95%CI 1.04-6.11 and OR 3.62; 95%CI 1.27-10.30, respectively). Additionally interaction between the 975C > G-ERalpha and Leu432Leu (4326C > C)-CYP1B1 or Leu432Val (4326C > G)-CYP1B1 variants also increased the risk (OR 4.68; 95%CI 1.81-12.07 and OR 6.00; 95%CI 2.19-16.47, respectively). CONCLUSIONS: The CYP1B1 and ERalpha genes may play a role in endometrial cancer and the Arg48Gly (142C > G) -CYP1B1 and 975C > G-ERalpha polymorphisms may be considered as independent, early diagnostic markers in this disease.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/genética , Carcinoma/genética , Neoplasias Endometriales/genética , Receptor alfa de Estrógeno/genética , Anciano , Citocromo P-450 CYP1B1 , Femenino , Regulación Neoplásica de la Expresión Génica , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Persona de Mediana Edad , Oportunidad Relativa , Polonia , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Análisis de Regresión , Factores de Riesgo , Población Blanca/genéticaRESUMEN
PURPOSE: Breast cancer is one of the major killers worldwide. Aberrant double-stranded break (DSB) repair leads to genomic instability, which is a hallmark of malignant cells. Double-stranded breaks are repaired in two pathways: homologous recombination (HR) and non-homologous DNA end joining (NHEJ). It is not known whether these repair pathways are affected in sporadic breast tumours. MATERIAL AND METHODS: In the present work the distribution of genotypes and frequency of alleles of the Ku70, A46922G (rs132793) polymorphism and Ligase IV, A6008G (Ile591Val) (rs2232641) polymorphism in breast cancer women were investigated. The genetic polymorphism analysis was performed using a DNA ABI PRISM 377 sequence detection system (Applied Biosystems) in 135 sporadic breast cancer cases. RESULTS: The distribution of the genotypes of the A46922G polymorphism of Ku70 in patients differed significantly (p < 0.05) from those predicted by the Hardy-Weinberg equilibrium. There were significant differences in the frequencies of alleles between the breast cancer subjects and controls (p < 0.05). However, the distribution of the genotypes of the A6008G polymorphism of Ligase IV in both controls and patients did not differ significantly (p > 0.05) from that predicted by the Hardy-Weinberg distribution. CONCLUSION: The results support the hypothesis that the A46922G polymorphism of the Ku70 gene may be associated with the incidence of breast cancer in women from the Lodz region of Poland.
Asunto(s)
Reparación del ADN , Polimorfismo Genético , Neoplasias de la Mama , ADN/genética , Roturas del ADN de Doble Cadena , Femenino , Humanos , LigasasRESUMEN
The RAD51 protein and its paralog, XRCC3, play an important role in the repair of DNA double-strand breaks (DSBs) by homologous recombination. Since DSBs may contribute to the pathogenesis of breast cancer and variability in DNA repair genes may be linked with some cancers, we performed a case-control study (135 cases and 175 controls) to check the association between the genotypes of the Thr241Met polymorphism of the XRCC3 gene and the 135G>C polymorphism of the RAD51 gene and breast cancer occurrence and progression. Genotypes were determined in peripheral blood lymphocytes by RFLP-PCR. We did not find any association between either polymorphism singly and breast cancer occurrence. Both polymorphisms were not related to tumor size, estrogen and progesterone receptors status, cancer type and grade. However, the Thr241Met genotype of the XRCC3 polymorphism slightly increased the risk of local metastasis in breast cancer patients (OR 2.56, 95% CI 1.27-5.17). The combined Thr241Met/135G>C genotype decreased the risk of breast cancer occurrence (OR 0.22, 95% CI 0.08-0.59). Our results suggest that the variability of the DNA homologous recombination repair genes RAD51 and XRCC3 may play a role in breast cancer occurrence and progression, but this role may be underlined by a mutual interaction between these genes.
Asunto(s)
Neoplasias de la Mama/genética , Reparación del ADN , Proteínas de Unión al ADN/genética , Polimorfismo Genético , Recombinasa Rad51/genética , Recombinación Genética , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Proteínas de Unión al ADN/metabolismo , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Persona de Mediana Edad , Recombinasa Rad51/metabolismoRESUMEN
The cytochrome P450 family (CYPs) enzymes play an important role in the metabolism of environmental carcinogens and of oestrogen and can affect breast cancer risk. We hypothesise that polymorphisms of CYP17 and CYP19 gene can predict higher incidence of breast cancer. In the present work the distribution of genotypes and frequency of alleles of the T/C polymorphism in promoter region of CYP17 and Trp/Arg polymorphism in codon 39 of CYP19 gene in breast cancer women were investigated. The genetic polymorphisms analysis was performed by amplifying DNA by PCR-RFLP methods in 100 sporadic breast cancer cases. The distribution of the genotypes of the T/C polymorphism of CYP17 in patients differed significantly (p < 0.05) from those predicted by the Hardy-Weinberg equilibrium. There were significant differences in the frequencies of alleles between the breast cancer subjects and controls (p < 0.05). However, the distribution of the genotypes of the Trp/Arg polymorphism of CYP19 in both control and patients did not differ significantly (p > 0.05) from those predicted by the Hardy-Weinberg distribution. The results support the hypothesis that the T/C polymorphism of CYP17 gene may be associated with the incidence of breast cancer in women from Lodz region of Poland.
Asunto(s)
Aromatasa/genética , Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/genética , Polimorfismo de Nucleótido Simple/genética , Esteroide 17-alfa-Hidroxilasa/genética , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/epidemiología , Carcinoma Ductal de Mama/epidemiología , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes/genética , Genotipo , Humanos , Incidencia , Persona de Mediana Edad , Polonia/epidemiología , Factores de RiesgoRESUMEN
AIM: Genetic polymorphism in XRCC1 and XRCC3 genes may influence DNA repair capacity and, in turn, confer predisposition to breast cancer. MATERIAL AND METHODS: In the present work the distribution of genotypes and frequency of alleles of the Arg194Trp and Arg399Gln polymorphism of XRCC1 and Trp241 Met polymorphism in XRCC3 in breast cancer women were analysed. Blood samples were obtained from 150 women with breast cancer and controls (n = 106). The polymorphisms were determined by PCR-RFLP methods. RESULTS: No association between XRCC1 Arg399Gln and Arg194Trp genotype and breast cancer risk was observed. The distribution of the genotypes of the Trp241 Met polymorphism of XRCC3 in both controls and patients did not differ significantly (p > 0.05) from those predicted by the Hardy-Weinberg distribution. There were no significant differences (p > 0.05) in genotype distributions and allele frequencies between subgroups assigned to histological stage. CONCLUSION: The results suggest that the Arg194Trp and Arg399Gln polymorphism of the XRCC1 gene as well as Trp241 Met polymorphism in XRCC3 may not be linked with appearance and development of breast cancer.
Asunto(s)
Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/genética , Reparación del ADN , Proteínas de Unión al ADN/genética , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/sangre , Carcinoma Ductal de Mama/patología , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Persona de Mediana Edad , Polonia , Polimorfismo de Longitud del Fragmento de Restricción , Posmenopausia , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos XRESUMEN
In this study we tested the hypothesis that dantrolene, an established inhibitor of the skeletal muscle isoform of the ryanodine receptor, may interfere with activity of NMDA receptors in neurons. We assessed the effects of dantrolene on [(3)H]MK-801 and [(3)H]glycine binding to isolated rat cortical membranes. Dantrolene inhibited [(3)H]MK-801 binding in the presence of 100 microM NMDA with an IC(50) of 58.4 microM. The IC(50) value increased to 99.6, 343.0 and 364.6 microM in the presence of 10, 30 and 50 microM glycine, respectively, suggesting that dantrolene competes with glycine for binding site at the NMDA receptor complex. A binding assay using [(3)H]glycine confirmed this supposition: dantrolene inhibited strychnine-insensitive glycine binding in a dose-dependent way. Thus, our results show that dantrolene at concentrations of 50-100 microM and higher blocks the glycine binding site of the NMDA receptor complex and in this way inhibits activation of the NMDA ion channel. These data reveal a new mechanism of dantrolene action in neuronal tissue. Our results also suggest that the neuroprotective effect of dantrolene may be at least partly explained by its activity as a non-competitive antagonist of NMDA receptors.
Asunto(s)
Membrana Celular/metabolismo , Dantroleno/farmacología , Fármacos Neuroprotectores/farmacología , Receptores de Glicina/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Animales , Sitios de Unión/efectos de los fármacos , Unión Competitiva/efectos de los fármacos , Membrana Celular/química , Corteza Cerebral/química , Citoprotección , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/farmacología , Glicina/farmacología , Hipocampo/química , Relajantes Musculares Centrales/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Receptores de Glicina/química , Receptores de Glicina/metabolismo , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/metabolismo , Estricnina/farmacología , Fracciones Subcelulares/químicaRESUMEN
Down's syndrome (DS) is associated with the presence of a third 21 chromosome and is generally considered as a non-cancer-prone genetic disease. However, leukaemias occur more frequently in children with the syndrome than in general population and there is an open question, whether the presence of an additional chromosome may contribute to genomic instability, which, in turn, may play a role in a higher susceptibility to cancer and leukaemias in particular. In order to assess genomic instability associated with the presence of a third 21 chromosome, we determined the level of endogenous DNA damage and susceptibility to a genotoxic stress-inducing factor, hydrogen peroxide and N-methyl-N'-nitro-N-nitrosoguanidyne (MNNG) as well as the ability to remove DNA damage in the peripheral blood lymphocytes of children with DS and healthy kids. The level of DNA damage and the kinetics of DNA repair were evaluated by alkaline comet assay. Oxidative DNA damage was assayed with DNA repair enzymes: endonuclease III-like NTH1 and formamidopyrimidine-DNA glycosylase. The cells taken from children with DS did not display an effective DNA repair after treatment with 10 mM hydrogen peroxide. No difference in the sensitivity to DNA-damaging agents and the efficacy of DNA repair due to age and gender in DS children was observed. These results suggest that children with DS may be characterized by the increased sensitivity to the DNA-damaging agents impaired cellular reaction to DNA damage, which, in turn, may increase the probability of cancers in these children. Therefore, a special care to avoid exposure to potential mutagenic factor my be considered in these children.
Asunto(s)
Daño del ADN , Reparación del ADN , Síndrome de Down/genética , Adolescente , Niño , Preescolar , Ensayo Cometa , Femenino , Humanos , Peróxido de Hidrógeno/farmacología , Masculino , Metilnitronitrosoguanidina/farmacologíaRESUMEN
UNLABELLED: Estrogens play a crucial role in the pathogenesis and progression of breast and endometrial cancer. The gene ER-alpha is polymorphic and gene variability could contribute to the level of protein biosynthesis. In the present work the distribution of genotypes and frequency of alleles of the Pvull polymorphism and Xbal polymorphism of ER-alpha gene in subjects with breast cancer were investigated. MATERIAL AND METHODS: Blood samples were obtained from 103 postmenopausal women with breast cancer. The polymorphisms were determined by PCR-RFLP. RESULTS: The distribution of the genotypes of Pvull and Xbal polymorphism of ER-alpha in both control and patients did not differ significantly (p > 0.05) from those predicted by the Hardy-Weinberg distribution. There were no significant differences (p > 0.05) in genotype distributions and allele frequencies between subgroups assigned to histological stage. CONCLUSIONS: The results suggest that the Pvull polymorphism of ER-alpha gene as well as Xbal polymorphism may not be linked with appearance and development of breast cancer.
Asunto(s)
Neoplasias de la Mama/genética , Receptor alfa de Estrógeno/genética , Polimorfismo Genético , Anciano , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Persona de Mediana Edad , PosmenopausiaRESUMEN
Common polymorphism in DNA repair genes may alter protein function and an individual's capacity to repair damaged DNA; deficits in repair capacity may lead to genetic instability and carcinogenesis. In present work we investigated the association between XPD Lys751Gln polymorphism and breast cancer progression. The polymorphism was analysed in breast cancer patients (n = 92) in blood. Blood samples from age matched healthy women served as control (n = 110). XPD genotypes were measured by PCR-RFLP. The distribution of the genotypes of the Lys751Gln polymorphism in patients differed significantly (p < 0.05) from those predicted by the Hardy-Weinberg equilibrium. There were significant differences in the frequencies of alleles between the breast cancer subjects and controls (p < 0.05). The results support the hypothesis that the Lys751Gln polymorphism of XPD gene may be associated with the incidence of breast cancer.
Asunto(s)
Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Longitud del Fragmento de Restricción , Proteína de la Xerodermia Pigmentosa del Grupo D/genética , Adulto , Anciano , Femenino , Genotipo , Humanos , Persona de Mediana Edad , Reacción en Cadena de la PolimerasaRESUMEN
The aim of the study was to present a new EIN classification of premalignant endometrial lesions. The diagnosis of precancerous disease of the endometrium remains non-standardized because the most widely used World Health Organisation classification is a poorly reproducible system, which does not specify objective architectural criteria for each category of hyperplasia and does not correspond to an appropriate clinical management (undertreatment, overtreatment of the lesions). The new proposed EIN diagnostic schema, based on integrated morphological, genetic molecular, objective histomorphometric (D-score) and clinical outcome studies, divides endometrial lesions into three categories: benign hyperplasia, endometrial intraepithelial neoplasia, and cancer.
Asunto(s)
Adenocarcinoma/clasificación , Carcinoma in Situ/clasificación , Hiperplasia Endometrial/clasificación , Neoplasias Endometriales/clasificación , Lesiones Precancerosas/clasificación , Adenocarcinoma/patología , Carcinoma in Situ/patología , Hiperplasia Endometrial/patología , Neoplasias Endometriales/patología , Femenino , Humanos , Estadificación de Neoplasias , Lesiones Precancerosas/patología , Terminología como AsuntoRESUMEN
Mutations in the MMAC/PTEN (phosphatase and tensin homologue deleted on chromosome 10) gene are documented in cancers of the breast, prostate, ovary, colon, melanoma, glioblastoma, lymphoma and endometrium. In the present work MMAC/PTEN gene expression in women with endometrial adenocarcinoma (n=70) in RNA samples obtained from cancer tissue were investigated. Control DNA was obtained from 68 normal endometrial tissue. The MMAC/PTEN expression was determined by RT-PCR analysis. The expression of MMAC/PTEN gene in endometrial adenocarcinoma cases was significantly reduced compared to the expression in the normal samples (P < 0.05). Furthermore the significant difference (P < 0.05) was observed between the expression of MMAC/PTEN in stage III versus lower stages of endometrial cancer. The results support the hypothesis that the MMAC/PTEN gene expression may be associated with the incidence of endometrial cancer.
Asunto(s)
Adenocarcinoma/genética , Biomarcadores de Tumor/genética , Neoplasias Endometriales/genética , Expresión Génica , Fosfohidrolasa PTEN/genética , Anciano , Femenino , Perfilación de la Expresión Génica , Humanos , Persona de Mediana Edad , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BRCA1 tumor suppressor gene encodes an 1863-amino acid gene product that is implicated in many cellular pathways including transcription, cell-cycle checkpoint control, apoptosis and DNA repair. A role of apoptosis and BRCA1 germ-line mutation in breast cancer appearance was investigated in this study by both apoptosis frequency analysis and mutation screening of BRCA1 among breast cancer cases. Blood was obtained from 40 women with node-negative and node-positive ductal breast carcinomas with uniform tumor size. The blood samples from age matched healthy women (n=42) served as control. BRCA1 gene mutations were determined by PCR-RFLP methods. The apoptotic peripheral blood cells were detected by agarose gel electrophoresis. The apoptotic cells were identified in 30% (12/40) of the patients. There were no significant differences in apoptosis frequencies between patients and controls (P > 0.05). Three mutations of BRCA1 gene were identified in apoptosis positive samples from breast cancer women; one Ex20insC and two ExII17delA. Our study implies that apoptosis may be involved not only in sporadic breast carcinoma without BRCA1 mutations, but also in BRCA1-associated breast carcinoma.
Asunto(s)
Apoptosis/fisiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patología , Proteínas Portadoras/genética , Adulto , Femenino , Mutación de Línea Germinal , Humanos , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Ubiquitina-Proteína LigasasRESUMEN
UNLABELLED: One of the reasons for not commencing or withdrawal of HRT in women is their fear for breast and endometrial cancers. Does ultrasonographic valuation guarantee sufficiently patient's safety? Most investigators do not recommend further endometrial diagnostics with endometrial thickness less than 4 mm. Endometrial biopsy is advised in cases of irregular uterine bleedings with normal endometrial image or when any endometrial pathology is suspected. In Poland the most frequently performed procedure of endometrial diagnostics is D&C. Our proposition was to offer endometrial biopsies to all patients who were taken HRT for more than 5 years or, despite having strong climacteric ailments, refused to take it because of their cancerophobia. AIM OF STUDY: To evaluate the usefulness of aspiration endometrial biopsy in women after menopause qualified for HRT. MATERIAL AND METHODS: In 84 females, being postmenopausal (amenorrhoeic for at least 12 months) and qualified for HRT, aspiration endometrial biopsies were performed in outpatient clinics. Age of women ranged 46-63 years, mean 57.3. Attained results were compared to ultrasonographic endometrial evaluation. Such factors as patient's age, menopausal age (years from last menstrual period) and previous administration of HRT were taken into our account (maintaining a 3-month wash-out interval). In 74% of women we have got a material being sufficient for histological evaluation. Form clinical point of view the most important for us was to exclude a proliferative or neoplastic process within endometrium. One of endometrial polyps was omitted in USG study, we were surprised also while detecting endometrial carcinoma cells in endometrium below 3.5 mm. In one postoperative slide the cells of endometrial ovarian carcinoma (with infiltrated Fallopian tube) were detected. CONCLUSION: Endometrial biopsy seems to be a useful, effective and cheap method of endometrial diagnostics also in women after menopause.