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1.
Hum Reprod ; 38(10): 2028-2038, 2023 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-37553222

RESUMEN

STUDY QUESTION: In children affected by rhabdoid tumors (RT), are there clinical, therapeutic, and/or (epi-)genetic differences between those conceived following ART compared to those conceived without ART? SUMMARY ANSWER: We detected a significantly elevated female predominance, and a lower median age at diagnosis, of children with RT conceived following ART (RT_ART) as compared to other children with RT. WHAT IS KNOWN ALREADY: Anecdotal evidence suggests an association of ART with RT. STUDY DESIGN, SIZE, DURATION: This was a multi-institutional retrospective survey. Children with RT conceived by ART were identified in our EU-RHAB database (n = 11/311 children diagnosed between January 2010 and January 2018) and outside the EU-RHAB database (n = 3) from nine different countries. A population-representative German EU-RHAB control cohort of children with RTs conceived without ART (n = 211) (EU-RHAB control cohort) during the same time period was used as a control cohort for clinical, therapeutic, and survival analyses. The median follow-up time was 11.5 months (range 0-120 months) for children with RT_ART and 18.5 months (range 0-153 months) for the EU-RHAB control cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analyzed 14 children with RT_ART diagnosed from January 2010 to January 2018. We examined tumors and matching blood samples for SMARCB1 mutations and copy number alterations using FISH, multiplex ligation-dependent probe amplification, and DNA sequencing. DNA methylation profiling of tumor and/or blood samples was performed using DNA methylation arrays and compared to respective control cohorts of similar age (n = 53 tumors of children with RT conceived without ART, and n = 38 blood samples of children with no tumor born small for gestational age). MAIN RESULTS AND THE ROLE OF CHANCE: The median age at diagnosis of 14 individuals with RT_ART was 9 months (range 0-66 months), significantly lower than the median age of patients with RT (n = 211) in the EU-RHAB control cohort (16 months (range 0-253), P = 0.03). A significant female predominance was observed in the RT_ART cohort (M:F ratio: 2:12 versus 116:95 in EU-RHAB control cohort, P = 0.004). Eight of 14 RT_ART patients were diagnosed with atypical teratoid rhabdoid tumor, three with extracranial, extrarenal malignant rhabdoid tumor, one with rhabdoid tumor of the kidney and two with synchronous tumors. The location of primary tumors did not differ significantly in the EU-RHAB control cohort (P = 0.27). Six of 14 RT_ART patients presented with metastases at diagnosis. Metastatic stage was not significantly different from that within the EU-RHAB control cohort (6/14 vs 88/211, P = 1). The incidence of pathogenic germline variants was five of the 12 tested RT_ART patients and, thus, not significantly different from the EU-RHAB control cohort (5/12 versus 36/183 tested, P = 0.35). The 5-year overall survival (OS) and event free survival (EFS) rates of RT_ART patients were 42.9 ± 13.2% and 21.4 ± 11%, respectively, and thus comparable to the EU-RHAB control cohort (OS 41.1 ± 3.5% and EFS 32.1 ± 3.3). We did not find other clinical, therapeutic, outcome factors distinguishing patients with RT_ART from children with RTs conceived without ART (EU-RHAB control cohort). DNA methylation analyses of 10 tumors (atypical teratoid RT = 6, extracranial, extrarenal malignant RT = 4) and six blood samples from RT_ART patients showed neither evidence of a general DNA methylation difference nor underlying imprinting defects, respectively, when compared to a control group (n = 53 RT samples of patients without ART, P = 0.51, n = 38 blood samples of patients born small for gestational age, P = 0.1205). LIMITATIONS, REASONS FOR CAUTION: RTs are very rare malignancies and our results are based on a small number of children with RT_ART. WIDER IMPLICATIONS OF THE FINDINGS: This cohort of patients with RT_ART demonstrated a marked female predominance, and a rather low median age at diagnosis even for RTs. Other clinical, treatment, outcome, and molecular factors did not differ from those conceived without ART (EU-RHAB control cohort) or reported in other series, and there was no evidence for imprinting defects. Long-term survival is achievable even in cases with pathogenic germline variants, metastatic disease at diagnosis, or relapse. The female preponderance among RT_ART patients is not yet understood and needs to be evaluated, ideally in larger international series. STUDY FUNDING/COMPETING INTEREST(S): M.C.F. is supported by the 'Deutsche Kinderkrebsstiftung' DKS 2020.10, by the 'Deutsche Forschungsgemeinschaft' DFG FR 1516/4-1 and by the Deutsche Krebshilfe 70113981. R.S. received grant support by Deutsche Krebshilfe 70114040 and for infrastructure by the KinderKrebsInitiative Buchholz/Holm-Seppensen. P.D.J. is supported by the Else-Kroener-Fresenius Stiftung and receives a Max-Eder scholarship from the Deutsche Krebshilfe. M.H. is supported by DFG (HA 3060/8-1) and IZKF Münster (Ha3/017/20). BB is supported by the 'Deutsche Kinderkrebsstiftung' DKS 2020.05. We declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

2.
Haematologica ; 108(2): 543-554, 2023 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-35522148

RESUMEN

Histone methylation-modifiers, such as EZH2 and KMT2D, are recurrently altered in B-cell lymphomas. To comprehensively describe the landscape of alterations affecting genes encoding histone methylation-modifiers in lymphomagenesis we investigated whole genome and transcriptome data of 186 mature B-cell lymphomas sequenced in the ICGC MMML-Seq project. Besides confirming common alterations of KMT2D (47% of cases), EZH2 (17%), SETD1B (5%), PRDM9 (4%), KMT2C (4%), and SETD2 (4%), also identified by prior exome or RNA-sequencing studies, we here found recurrent alterations to KDM4C in chromosome 9p24, encoding a histone demethylase. Focal structural variation was the main mechanism of KDM4C alterations, and was independent from 9p24 amplification. We also identified KDM4C alterations in lymphoma cell lines including a focal homozygous deletion in a classical Hodgkin lymphoma cell line. By integrating RNA-sequencing and genome sequencing data we predict that KDM4C structural variants result in loss-offunction. By functional reconstitution studies in cell lines, we provide evidence that KDM4C can act as a tumor suppressor. Thus, we show that identification of structural variants in whole genome sequencing data adds to the comprehensive description of the mutational landscape of lymphomas and, moreover, establish KDM4C as a putative tumor suppressive gene recurrently altered in subsets of B-cell derived lymphomas.


Asunto(s)
Linfoma de Células B , Linfoma , Humanos , Histonas/metabolismo , Histona Demetilasas/genética , Homocigoto , Eliminación de Secuencia , Linfoma/genética , Linfoma de Células B/genética , Secuenciación Completa del Genoma , ARN , Histona Demetilasas con Dominio de Jumonji/genética , Histona Demetilasas con Dominio de Jumonji/química , Histona Demetilasas con Dominio de Jumonji/metabolismo , N-Metiltransferasa de Histona-Lisina/genética
3.
Nature ; 541(7635): 81-86, 2017 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-28002404

RESUMEN

Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10-7, range P = 9.2 × 10-8 to 6.0 × 10-46; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10-6, range P = 5.5 × 10-6 to 6.1 × 10-35, n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 × 10-54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.


Asunto(s)
Adiposidad/genética , Índice de Masa Corporal , Metilación de ADN/genética , Diabetes Mellitus Tipo 2/genética , Epigénesis Genética , Epigenómica , Estudio de Asociación del Genoma Completo , Obesidad/genética , Tejido Adiposo/metabolismo , Pueblo Asiatico/genética , Sangre/metabolismo , Estudios de Cohortes , Diabetes Mellitus Tipo 2/complicaciones , Europa (Continente)/etnología , Femenino , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , India/etnología , Masculino , Obesidad/sangre , Obesidad/complicaciones , Sobrepeso/sangre , Sobrepeso/complicaciones , Sobrepeso/genética , Población Blanca/genética
4.
Nutr Metab Cardiovasc Dis ; 32(6): 1502-1510, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35450790

RESUMEN

BACKGROUND AND AIM: Childhood obesity is an emerging problem often leading to earlier onset of non-communicable diseases in later life. Biomarkers to identify individual risk scores are insufficient in routine clinical practice, which is related to the need for easily sampled, non-invasive survey methods in children. We aimed to investigate and strengthen possible pro-inflammatory markers and epigenetic risk factors in saliva of obese children compared to lean controls. METHODS AND RESULTS: 19 overweight/obese (OC, 10.1 ± 1.9 years, BMI 27.7 ± 3.2 kg/m2) and 19 lean control children (CC, 9.7 ± 2.5 years, BMI 16.4 ± 1.8 kg/m2) participated in this explorative pilot study. Anthropometric measures, saliva and cheek swab samples were taken. Saliva profiles were examined for acute phase proteins (CRP and neopterin) and pro-inflammatory cytokines (IL-17a/IL-1ß/IL-6). Cheek swabs were analyzed to investigate DNA methylation differences with subsequent hierarchical cluster and principal component analyses (PCA). Saliva analysis showed significant increased CRP concentrations in OC compared to CC (p < 0.001). There were no significant differences, but high intra-individual values in neopterin, IL-17a, IL-1ß and IL-6. An unsupervised PCA of CpG loci with high variance (σ/σmax > 0.2) clearly separated OC and CC according to their methylation pattern. Furthermore, a supervised approach revealed 7125 significantly differentially methylated loci, whose corresponding genes were significantly enriched for genes playing roles in e.g., cellular signalling, cytoskeleton organization and cell motility. CONCLUSIONS: CRP and methylation status determinations in saliva are suitable as non-invasive methods for early detection of risks for non-communicable diseases in children/adolescents and might be a useful supplementary approach in the routine clinical practice/monitoring.


Asunto(s)
Enfermedades no Transmisibles , Obesidad Infantil , Adolescente , Biomarcadores/metabolismo , Niño , Marcadores Genéticos , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Neopterin/genética , Neopterin/metabolismo , Obesidad Infantil/diagnóstico , Obesidad Infantil/epidemiología , Obesidad Infantil/genética , Proyectos Piloto , Saliva/metabolismo
5.
Dev Psychopathol ; 34(3): 864-874, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-33461631

RESUMEN

DNA methylation of the elongation of very long chain fatty acids protein 2 (ELOVL2) was suggested as a biomarker of biological aging, while childhood maltreatment (CM) has been associated with accelerated biological aging. We investigated the association of age and CM experiences with ELOVL2 methylation in peripheral blood mononuclear cells (PBMC). Furthermore, we investigated ELOVL2 methylation in the umbilical cord blood mononuclear cells (UBMC) of newborns of mothers with and without CM. PBMC and UBMC were isolated from 113 mother-newborn dyads and genomic DNA was extracted. Mothers with and without CM experiences were recruited directly postpartum. Mass array spectrometry and pyrosequencing were used for methylation analyses of ELOVL2 intron 1, and exon 1 and 5' end, respectively. ELOVL2 5' end and intron 1 methylation increased with higher age but were not associated with CM experiences. On the contrary, overall ELOVL2 exon 1 methylation increased with higher CM, but these changes were minimal and did not increase with age. Maternal CM experiences and neonatal methylation of ELOVL2 intron 1 or exon 1 were not significantly correlated. Our study suggests region-specific effects of chronological age and experienced CM on ELOVL2 methylation and shows that the epigenetic biomarker for age within the ELOVL2 gene does not show accelerated biological aging years after CM exposure.


Asunto(s)
Maltrato a los Niños , Metilación de ADN , Envejecimiento , Niño , Elongasas de Ácidos Grasos/genética , Femenino , Humanos , Recién Nacido , Leucocitos Mononucleares
6.
Respir Res ; 21(1): 274, 2020 Oct 19.
Artículo en Inglés | MEDLINE | ID: mdl-33076907

RESUMEN

BACKGROUND: To date, most studies involving high-throughput analyses of sputum in asthma and COPD have focused on identifying transcriptomic signatures of disease. No whole-genome methylation analysis of sputum cells has been performed yet. In this context, the highly variable cellular composition of sputum has potential to confound the molecular analyses. METHODS: Whole-genome transcription (Agilent Human 4 × 44 k array) and methylation (Illumina 450 k BeadChip) analyses were performed on sputum samples of 9 asthmatics, 10 healthy and 10 COPD subjects. RNA integrity was checked by capillary electrophoresis and used to correct in silico for bias conferred by RNA degradation during biobank sample storage. Estimates of cell type-specific molecular profiles were derived via regression by quadratic programming based on sputum differential cell counts. All analyses were conducted using the open-source R/Bioconductor software framework. RESULTS: A linear regression step was found to perform well in removing RNA degradation-related bias among the main principal components of the gene expression data, increasing the number of genes detectable as differentially expressed in asthma and COPD sputa (compared to controls). We observed a strong influence of the cellular composition on the results of mixed-cell sputum analyses. Exemplarily, upregulated genes derived from mixed-cell data in asthma were dominated by genes predominantly expressed in eosinophils after deconvolution. The deconvolution, however, allowed to perform differential expression and methylation analyses on the level of individual cell types and, though we only analyzed a limited number of biological replicates, was found to provide good estimates compared to previously published data about gene expression in lung eosinophils in asthma. Analysis of the sputum methylome indicated presence of differential methylation in genomic regions of interest, e.g. mapping to a number of human leukocyte antigen (HLA) genes related to both major histocompatibility complex (MHC) class I and II molecules in asthma and COPD macrophages. Furthermore, we found the SMAD3 (SMAD family member 3) gene, among others, to lie within differentially methylated regions which has been previously reported in the context of asthma. CONCLUSIONS: In this methodology-oriented study, we show that methylation profiling can be easily integrated into sputum analysis workflows and exhibits a strong potential to contribute to the profiling and understanding of pulmonary inflammation. Wherever RNA degradation is of concern, in silico correction can be effective in improving both sensitivity and specificity of downstream analyses. We suggest that deconvolution methods should be integrated in sputum omics analysis workflows whenever possible in order to facilitate the unbiased discovery and interpretation of molecular patterns of inflammation.


Asunto(s)
Asma/genética , Epigenoma/fisiología , Perfilación de la Expresión Génica/métodos , Enfermedad Pulmonar Obstructiva Crónica/genética , Esputo/fisiología , Adulto , Anciano , Asma/diagnóstico , Asma/metabolismo , Femenino , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Masculino , Persona de Mediana Edad , Análisis por Matrices de Proteínas/métodos , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Análisis de Secuencia de ARN/métodos , Esputo/química
7.
Genes Chromosomes Cancer ; 58(1): 66-69, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30284345

RESUMEN

Primary lymphomas of the central nervous system (PCNSL) are diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). We here performed array-based DNA methylation analyses of 26 PCNSL and 78 DLBCL and validated our findings in an independent dataset. We identified 2847 CpGs differentially methylated between PCNSL and non-CNS-DLBCL. Neither a supervised analysis using these CpGs nor application of 3 CpG classifiers selected for class separation unambiguously separated PCNSL from non-CNS-DLBCL. Remarkably, 6/78 non-CNS-DLBCL consistently segregated with PCNSL, which displayed molecular features typical for PCNSL. Our findings suggest that a subset of non-CNS-DLBCL exists which molecularly resembles PCNSL.


Asunto(s)
Neoplasias del Sistema Nervioso Central/diagnóstico , Metilación de ADN/genética , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma/diagnóstico , Adulto , Anciano , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Diagnóstico Diferencial , Femenino , Humanos , Linfocitos , Linfoma/genética , Linfoma/patología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad
8.
Br J Haematol ; 185(1): 79-88, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30681722

RESUMEN

Loss of B cell-specific transcription factors (TFs) and the resulting loss of B-cell phenotype of Hodgkin and Reed-Sternberg (HRS) cells is a hallmark of classical Hodgkin lymphoma (cHL). Here we have analysed two members of ETS domain containing TFs, ELF1 and ELF2, regarding (epi)genomic changes as well as gene and protein expression. We observed absence or lower levels of ELF1 protein in HRS cells of 31/35 (89%) cases compared to the bystander cells and significant (P < 0·01) downregulation of the gene on mRNA as well as protein level in cHL compared to non-cHL cell lines. However, no recurrent loss of ELF2 protein was observed. Moreover, ELF1 was targeted by heterozygous deletions combined with hypermethylation of the remaining allele(s) in 4/7 (57%) cell lines. Indeed, DNA hypermethylation (range 95-99%, mean 98%) detected in the vicinity of the ELF1 transcription start site was found in all 7/7 (100%) cHL cell lines. Similarly, 5/18 (28%) analysed primary biopsies carried heterozygous deletions of the gene. We demonstrate that expression of ELF1 is impaired in cHL through genetic and epigenetic alterations, and thus, it may represent an additional member of a TF network whose downregulation contributes to the loss of B-cell phenotype of HRS cells.


Asunto(s)
Motivo ETS , Eliminación de Gen , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , Linfocitos B/metabolismo , Linfocitos B/patología , Biopsia , Línea Celular Tumoral , Metilación de ADN , Motivo ETS/genética , Heterocigoto , Enfermedad de Hodgkin/metabolismo , Humanos , Inmunohistoquímica , Mutación , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de Transcripción/química , Factores de Transcripción/metabolismo
9.
Int J Cancer ; 143(12): 3061-3070, 2018 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-29974462

RESUMEN

Aging affects the core processes of almost every organism, and the functional decline at the cellular and tissue levels influences disease development. Recently, it was shown that the methylation of certain CpG dinucleotides correlates with chronological age and that this epigenetic clock can be applied to study aging-related effects. We investigated these molecular age loci in non-small cell lung cancer (NSCLC) tissues from patients with adenocarcinomas (AC) and squamous cell carcinomas (SQC) as well as in matched tumor-free lung tissue. In both NSCLC subtypes, the calculated epigenetic age did not correlate with the chronological age. In particular, SQC exhibited rejuvenation compared to the corresponding normal lung tissue as well as with the chronological age of the donor. Moreover, the younger epigenetic pattern was associated with a trend toward stem cell-like gene expression patterns. These findings show deep phenotypic differences between the tumor entities AC and SQC, which might be useful for novel therapeutic and diagnostic approaches.


Asunto(s)
Envejecimiento/genética , Carcinoma de Células Escamosas/genética , Epigénesis Genética , Neoplasias Pulmonares/genética , Pulmón/metabolismo , Adenocarcinoma del Pulmón/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Islas de CpG , Metilación de ADN , Humanos , Persona de Mediana Edad , Transcripción Genética
10.
BMC Cancer ; 18(1): 796, 2018 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-30081852

RESUMEN

BACKGROUND: ADAMs (a disintegrin and metalloproteinase) have long been associated with tumor progression. Recent findings indicate that members of the closely related ADAMTS (ADAMs with thrombospondin motifs) family are also critically involved in carcinogenesis. Gene silencing through DNA methylation at CpG loci around e.g. transcription start or enhancer sites is a major mechanism in cancer development. Here, we aimed at identifying genes of the ADAM and ADAMTS family showing altered DNA methylation in the development or colorectal cancer (CRC) and other epithelial tumors. METHODS: We investigated potential changes of DNA methylation affecting ADAM and ADAMTS genes in 117 CRC, 40 lung cancer (LC) and 15 oral squamous-cell carcinoma (SCC) samples. Tumor tissue was analyzed in comparison to adjacent non-malignant tissue of the same patients. The methylation status of 1145 CpGs in 51 ADAM and ADAMTS genes was measured with the HumanMethylation450 BeadChip Array. ADAMTS16 protein expression was analyzed in CRC samples by immunohistochemistry. RESULTS: In CRC, we identified 72 CpGs in 18 genes which were significantly affected by hyper- or hypomethylation in the tumor tissue compared to the adjacent non-malignant tissue. While notable/frequent alterations in methylation patterns within ADAM genes were not observed, conspicuous changes were found in ADAMTS16 and ADAMTS2. To figure out whether these differences would be CRC specific, additional LC and SCC tissue samples were analyzed. Overall, 78 differentially methylated CpGs were found in LC and 29 in SCC. Strikingly, 8 CpGs located in the ADAMTS16 gene were commonly differentially methylated in all three cancer entities. Six CpGs in the promoter region were hypermethylated, whereas 2 CpGs in the gene body were hypomethylated indicative of gene silencing. In line with these findings, ADAMTS16 protein was strongly expressed in globlet cells and colonocytes in control tissue but not in CRC samples. Functional in vitro studies using the colorectal carcinoma cell line HT29 revealed that ADAMTS16 expression restrained tumor cell proliferation. CONCLUSIONS: We identified ADAMTS16 as novel gene with cancer-specific promoter hypermethylation in CRC, LC and SCC patients implicating ADAMTS16 as potential biomarker for these tumors. Moreover, our results provide evidence that ADAMTS16 may have tumor suppressor properties.


Asunto(s)
Proteínas ADAMTS/genética , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Metilación de ADN , Neoplasias Pulmonares/genética , Neoplasias de la Boca/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Proteínas ADAMTS/metabolismo , Biomarcadores de Tumor/metabolismo , Proliferación Celular , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/patología , Islas de CpG , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Células HT29 , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Neoplasias de la Boca/enzimología , Neoplasias de la Boca/patología , Regiones Promotoras Genéticas , Carcinoma de Células Escamosas de Cabeza y Cuello/enzimología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología
11.
Pediatr Blood Cancer ; 64(3)2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27786413

RESUMEN

Deregulation of the epigenome is an important pathogenetic mechanism in acute lymphoblastic leukemia (ALL) with lysine (K)-specific methyltransferase 2A rearrangement (KMT2Ar). We performed array-based DNA methylation profiling of KMT2Ar ALL cells from 26 children in comparison to normal B-cell precursors. Significant changes in DNA methylation in KMT2Ar ALL were identified in 2,545 CpG loci, influenced by age and the translocation partners AFF1 and MLLT1. In KMT2Ar ALL, DNA methylation loss was enriched at enhancers and for certain transcription factor binding sites such as BCL11A, EBF, and MEF2A. In summary, DNA methylation changes in KMT2Ar ALL target enhancers, genes involved in leukemogenesis and normal hematopoiesis, as well as transcription factor networks.


Asunto(s)
Biomarcadores de Tumor/genética , Metilación de ADN , Perfilación de la Expresión Génica , Reordenamiento Génico , N-Metiltransferasa de Histona-Lisina/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Linfocitos B/metabolismo , Estudios de Casos y Controles , Hibridación Genómica Comparativa , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Pronóstico , Regiones Promotoras Genéticas/genética
12.
Proc Natl Acad Sci U S A ; 111(43): 15538-43, 2014 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-25313081

RESUMEN

Because of the dearth of biomarkers of aging, it has been difficult to test the hypothesis that obesity increases tissue age. Here we use a novel epigenetic biomarker of aging (referred to as an "epigenetic clock") to study the relationship between high body mass index (BMI) and the DNA methylation ages of human blood, liver, muscle, and adipose tissue. A significant correlation between BMI and epigenetic age acceleration could only be observed for liver (r = 0.42, P = 6.8 × 10(-4) in dataset 1 and r = 0.42, P = 1.2 × 10(-4) in dataset 2). On average, epigenetic age increased by 3.3 y for each 10 BMI units. The detected age acceleration in liver is not associated with the Nonalcoholic Fatty Liver Disease Activity Score or any of its component traits after adjustment for BMI. The 279 genes that are underexpressed in older liver samples are highly enriched (1.2 × 10(-9)) with nuclear mitochondrial genes that play a role in oxidative phosphorylation and electron transport. The epigenetic age acceleration, which is not reversible in the short term after rapid weight loss induced by bariatric surgery, may play a role in liver-related comorbidities of obesity, such as insulin resistance and liver cancer.


Asunto(s)
Envejecimiento/genética , Epigénesis Genética , Hígado/metabolismo , Hígado/patología , Obesidad/genética , Envejecimiento/patología , Índice de Masa Corporal , Estudios Transversales , Metilación de ADN/genética , Bases de Datos Genéticas , Humanos , Modelos Genéticos , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reproducibilidad de los Resultados , Factores de Tiempo , Transcripción Genética , Pérdida de Peso/genética
13.
Birth Defects Res A Clin Mol Teratol ; 106(8): 724-8, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27223093

RESUMEN

BACKGROUND: The bladder exstrophy-epispadias complex (BEEC) is characterized by a spectrum of genitourinary malformations. Both classical bladder exstrophy and the most severe phenotype, exstrophy of the cloaca, display omphaloceles, a cardinal anomaly of some disorders caused by altered imprinting. Therefore, we hypothesized that BEEC in some patients could occur on the basis of an undiagnosed imprinting disorder. Such altered imprinting is associated with changes in the parent-of-origin-specific DNA methylation. METHODS: We analyzed the DNA methylation of 54 imprinted loci in 23 selected patients with different BEEC subtypes (epispadias n = 1, classical bladder exstrophy n = 10, exstrophy of the cloaca n = 12) using the Infinium HumanMethylation450 BeadChip. A total of 471,722 not imprinted autosomal CpG loci and 891 imprinted CpG loci were investigated. Findings were corroborated by methylation-specific-multiplex ligation-dependent probe amplification (MS-MLPA) and microsatellite analysis. RESULTS: No significant differences in the DNA methylation of the not imprinted and imprinted CpG were observed depending on subtype of BEEC. Nevertheless, in 1 of the 23 patients who displayed a classical bladder exstrophy, we detected hypomethylation of the imprinted PLAGL1 locus in chromosome 6q24. We verified this hypomethylation by MS-MLPA and showed further the methylation loss to be caused most likely by a mosaic epimutation. CONCLUSION: Considering that it is highly unlikely to detect a PLAGL1 epimutation among 23 individuals given the low incidence of this alteration in the population, our observations further support a link between BEEC and imprinting disorders. Birth Defects Research (Part A) 106:724-728, 2016. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Extrofia de la Vejiga/genética , Proteínas de Ciclo Celular/genética , Cromosomas Humanos Par 6/química , Metilación de ADN , Epispadias/genética , Impresión Genómica , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Adolescente , Extrofia de la Vejiga/diagnóstico , Extrofia de la Vejiga/patología , Niño , Preescolar , Estudios de Cohortes , Islas de CpG , Epispadias/diagnóstico , Epispadias/patología , Femenino , Expresión Génica , Sitios Genéticos , Humanos , Masculino , Repeticiones de Microsatélite , Reacción en Cadena de la Polimerasa Multiplex
14.
J Med Genet ; 51(6): 407-12, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24721835

RESUMEN

BACKGROUND: In a subset of imprinting disorders caused by epimutations, multiple imprinted loci are affected. Familial occurrence of multilocus imprinting disorders is rare. PURPOSE/OBJECTIVE: We have investigated the clinical and molecular features of a familial DNA-methylation disorder. METHODS: Tissues of affected individuals and blood samples of family members were investigated by conventional and molecular karyotyping. Sanger sequencing and RT-PCR of imprinting-associated genes (NLRP2, NLRP7, ZFP57, KHDC3L, DNMT1o), exome sequencing and locus-specific, array-based and genome-wide technologies to determine DNA-methylation were performed. RESULTS: In three offspring of a healthy couple, we observed prenatal onset of severe growth retardation and dysmorphism associated with altered DNA-methylation at paternally and maternally imprinted loci. Array-based analyses in various tissues of the offspring identified the DNA-methylation of 2.1% of the genes in the genome to be recurrently altered. Despite significant enrichment of imprinted genes (OR 9.49), altered DNA-methylation predominately (90.2%) affected genes not known to be imprinted. Sequencing of genes known to cause comparable conditions and exome sequencing in affected individuals and their ancestors did not unambiguously point to a causative gene. CONCLUSIONS: The family presented herein suggests the existence of a familial disorder of DNA-methylation affecting imprinted but also not imprinted gene loci potentially caused by a maternal effect mutation in a hitherto not identified gene.


Asunto(s)
Metilación de ADN/genética , Enfermedades Genéticas Congénitas/genética , Alelos , Análisis Mutacional de ADN , Epigenómica , Femenino , Humanos , Recién Nacido , Masculino , Linaje
15.
Genes Chromosomes Cancer ; 53(4): 309-16, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24446122

RESUMEN

T-cell prolymphocytic leukemia (T-PLL) is an aggressive post-thymic T-cell malignancy characterized by the recurrent inv(14)(q11q32)/t(14;14)(q11;q32) or t(X;14)(q28;q11) leading to activation of either the TCL1 or MTCP1 gene, respectively. However, these primary genetic events are insufficient to drive leukemogenesis. Recently, activating mutations in JAK3 have been identified in other T-cell malignancies. Since JAK3 is essential for T-cell maturation, we analyzed a cohort of 32 T-PLL patients for mutational hot spots in the JAK3 gene using a step-wise screening approach. We identified 14 mutations in 11 of 32 patients (34%). The most frequently detected mutation in our cohort was M511I (seen in 57% of cases) previously described as an activating change in other T-cell malignancies. Three patients carried two mutations in JAK3. In two patients M511I and R657Q were simultaneously detected and in another patient V674F and V678L. In the latter case we could demonstrate that the mutations were on the same allele in cis. Protein modeling and homology analyses of mutations present in other members of the JAK family suggested that these mutations likely activate JAK3, possibly by disrupting the activation loop and the interface between N and C lobes, increasing the accessibility of the catalytic loop. In addition, four of the 21 patients lacking a JAK3 point mutation presented an aberrant karyotype involving the chromosomal band 19p13 harboring the JAK3 locus. The finding of recurrent activating JAK3 mutations in patients with T-PLL could enable the use of JAK3 inhibitors to treat patients with this unfavorable malignancy who otherwise have a very poor prognosis.


Asunto(s)
Cromosomas Humanos Par 14/genética , Janus Quinasa 3/genética , Leucemia Prolinfocítica de Células T/genética , Anciano , Secuencia de Aminoácidos , Estudios de Cohortes , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , Mutación
16.
Lab Invest ; 94(8): 927-33, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24933424

RESUMEN

Alterations in the DNA methylome are characteristic for numerous diseases and a typical hallmark of cancer. Therefore, DNA methylation is currently under investigation in research labs and has also entered diagnostics. Recently, protocols like the BeadChip technology have become commercially available to study DNA methylation in an array format and semiquantitative fashion. However, it is known that fixation of the sample material with formalin prior to BeadChip analysis can affect the results. In this study we compared the influence of fixation on the outcome of BeadChip analysis. From six patients each a lung cancer tissue sample and a corresponding tumor-free lung tissue sample were collected. The samples were separated into three pieces. One piece of each sample was fixed with formalin, another one by the non-cross-linking HOPE technique (Hepes-glutamic acid buffer mediated Organic solvent Protection Effect). Subsequently, both became paraffin embedded. As a reference, the remaining third piece was cryopreserved. In addition we used three adenocarcinoma cell lines (H838, A549, and H1650) to validate the results from patient tissues. We show that using the HOPE technique instead of formalin largely prevents the introduction of formalin-fixation related artifacts. An ANOVA analysis significantly separated HOPE- and cryopreserved from formalin-fixed samples (FDR<0.05), while differences in the methylation data obtained from HOPE-fixed and cryopreserved material were minor. Consequently, HOPE fixation is superior to formalin fixation if a subsequent BeadChip analysis of paraffin-embedded sample material is intended.


Asunto(s)
Adenocarcinoma/metabolismo , Carcinoma de Células Escamosas/metabolismo , Metilación de ADN , ADN de Neoplasias/metabolismo , Neoplasias Pulmonares/metabolismo , Pulmón/metabolismo , Conservación de Tejido , Adenocarcinoma/patología , Anciano , Artefactos , Tampones (Química) , Carcinoma Adenoescamoso/metabolismo , Carcinoma Adenoescamoso/patología , Carcinoma de Células Grandes/metabolismo , Carcinoma de Células Grandes/prevención & control , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Criopreservación , ADN de Neoplasias/aislamiento & purificación , Femenino , Ácido Glutámico/química , HEPES/química , Humanos , Pulmón/patología , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Análisis de Matrices Tisulares , Fijación del Tejido
17.
Bioinformatics ; 29(13): 1600-6, 2013 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-23620359

RESUMEN

MOTIVATION: Protocols to generate strand-specific transcriptomes with next-generation sequencing platforms have been used by the scientific community roughly since 2008. Strand-specific reads allow for detection of antisense events and a higher resolution of expression profiles enabling extension of current transcript annotations. However, applications making use of this strandedness information are still scarce. RESULTS: Here we present a tool (Janus), which focuses on the identification of transcriptional active regions in antisense orientation to known and novel transcribed elements of the genome. Janus can compare the antisense events of multiple samples and assigns scores to identify mutual expression of either transcript in a sense/antisense pair, which could hint to regulatory mechanisms. Janus is able to make use of single-nucleotide variant (SNV) and methylation data, if available, and reports the sense to antisense ratio of regions in the vicinity of the identified genetic and epigenetic variation. Janus interrogates positions of heterozygous SNVs to identify strand-specific allelic imbalance. AVAILABILITY: Janus is written in C/C++ and freely available at http://www.ikmb.uni-kiel.de/janus/janus.html under terms of GNU General Public License, for both, Linux and Windows 64×. Although the binaries will work without additional downloads, the software depends on bamtools (https://github.com/pezmaster31/bamtools) for compilation. A detailed tutorial section is included in the first section of the supplemental material and included as brief readme.txt in the tutorial archive. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Asunto(s)
Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , ARN sin Sentido/biosíntesis , Programas Informáticos , Línea Celular Transformada , Metilación de ADN , Variación Genética , Humanos
19.
Histol Histopathol ; 39(7): 867-876, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38529720

RESUMEN

INTRODUCTION: Lung cancer is a major cause of cancer-related death worldwide and effective therapies, besides surgery, are available only for a small proportion of patients. Since cellular respiration is known to be broadly altered in malignant tumors, the cellular processes of respiration can be a potential therapeutic target. One important element of cellular respiration is creatine and its transport by the creatine transporter SLC6A8. Here we describe the expression of SLC6A8 at the RNA and protein level, epigenetic modifications as well as survival analysis in NSCLC tissues and matched controls. MATERIALS AND METHODS: We analyzed epigenetic modifications of the SLC68A gene in 32 patients, of which 18 were additionally analyzed by transcriptome analysis. The expression of SLC6A8 at the protein level was assessed by immunohistochemistry using an independent cohort and correlated with clinicopathological data including survival. Kaplan-Meier analysis was performed to analyze the possible effects of the transcriptional levels of SLC6A8 in another separate cohort (n=1925). RESULTS: SLC6A8 loci are epigenetically modified in NSCLC compared with tumor-free controls. SLC6A8 is upregulated in NSCLC at the RNA and protein level. High mRNA expression of SLC6A8 was associated with an overall poor prognosis in lung adenocarcinoma patients and displayed the strongest adverse prognostic effect in male smokers with adenocarcinomas. Results of transcriptome analysis were partially confirmed at the protein level. CONCLUSIONS: Our results suggest an important role of creatine and its transport via SLC6A8 in NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Epigénesis Genética , Neoplasias Pulmonares , Regulación hacia Arriba , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Regulación Neoplásica de la Expresión Génica , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/genética , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/metabolismo , Pronóstico , Estimación de Kaplan-Meier , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Adulto , Proteínas de Transporte de Membrana
20.
J Craniomaxillofac Surg ; 52(6): 748-754, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38582670

RESUMEN

Aim of this study was to demonstrate the influence of different analytical procedures and techniques on the resulting miRNA expression profile in healthy control subjects and tumor patients using the oral squamous cell carcinoma (OSCC) model and to demonstrate the technical and biological reproducibility. Body fluids such as saliva are suitable for non-invasive miRNA analysis because ubiquitously circulating miRNA can be found in them. It was technically possible to distinguish between healthy and diseased samples based on the miRNA expression profile found. Regardless of the methodology used, good technical reproducibility of the results seems to be achievable. On the other hand, biological reproducibility was inadequate, which is why prompt sampling and sequencing is recommended. The data indicate that malignant lesions can be detected using miRNA signatures extracted from saliva. This could stimulate further research to establish standardized protocols and kits for sample collection, miRNA extraction, sequencing and interpretation of results.


Asunto(s)
Carcinoma de Células Escamosas , MicroARNs , Neoplasias de la Boca , Saliva , Humanos , Saliva/química , MicroARNs/análisis , Neoplasias de la Boca/genética , Carcinoma de Células Escamosas/genética , Reproducibilidad de los Resultados , Femenino , Masculino , Persona de Mediana Edad
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