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1.
Int J Cancer ; 146(4): 999-1009, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31081934

RESUMO

Comparably little is known about breast cancer (BC) risks in women from families tested negative for BRCA1/2 mutations despite an indicative family history, as opposed to BRCA1/2 mutation carriers. We determined the age-dependent risks of first and contralateral breast cancer (FBC, CBC) both in noncarriers and carriers of BRCA1/2 mutations, who participated in an intensified breast imaging surveillance program. The study was conducted between January 1, 2005, and September 30, 2017, at 12 university centers of the German Consortium for Hereditary Breast and Ovarian Cancer. Two cohorts were prospectively followed up for incident FBC (n = 4,380; 16,398 person-years [PY], median baseline age: 39 years) and CBC (n = 2,993; 10,090 PY, median baseline age: 42 years). Cumulative FBC risk at age 60 was 61.8% (95% CI 52.8-70.9%) for BRCA1 mutation carriers, 43.2% (95% CI 32.1-56.3%) for BRCA2 mutation carriers and 15.7% (95% CI 11.9-20.4%) for noncarriers. FBC risks were significantly higher than in the general population, with incidence rate ratios of 23.9 (95% CI 18.9-29.8) for BRCA1 mutation carriers, 13.5 (95% CI 9.2-19.1) for BRCA2 mutation carriers and 4.9 (95% CI 3.8-6.3) for BRCA1/2 noncarriers. Cumulative CBC risk 10 years after FBC was 25.1% (95% CI 19.6-31.9%) for BRCA1 mutation carriers, 6.6% (95% CI 3.4-12.5%) for BRCA2 mutation carriers and 3.6% (95% CI 2.2-5.7%) for noncarriers. CBC risk in noncarriers was similar to women with unilateral BC from the general population. Further studies are needed to confirm whether less intensified surveillance is justified in women from BRCA1/2 negative families with elevated risk.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/epidemiologia , Predisposição Genética para Doença , Adulto , Fatores Etários , Neoplasias da Mama/genética , Monitoramento Epidemiológico , Feminino , Seguimentos , Alemanha/epidemiologia , Heterozigoto , Humanos , Incidência , Anamnese , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Medição de Risco , Fatores de Risco
2.
Nat Commun ; 10(1): 5348, 2019 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-31767839

RESUMO

There is increasing evidence for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children. To identify new risk variants for B-cell ALL (B-ALL) we conducted a meta-analysis with four GWAS (genome-wide association studies), totalling 5321 cases and 16,666 controls of European descent. We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P = 2.11 × 10-8), for high-hyperdiploid ALL at 5q31.1 (rs886285, P = 1.56 × 10-8) and 6p21.31 (rs210143 in BAK1, P = 2.21 × 10-8), and ETV6-RUNX1 ALL at 17q21.32 (rs10853104 in IGF2BP1, P = 1.82 × 10-8). Particularly notable are the pleiotropic effects of the BAK1 variant on multiple haematological malignancies and specific effects of IGF2BP1 on ETV6-RUNX1 ALL evidenced by both germline and somatic genomic analyses. Integration of GWAS signals with transcriptomic/epigenomic profiling and 3D chromatin interaction data for these leukaemia risk loci suggests deregulation of B-cell development and the cell cycle as central mechanisms governing genetic susceptibility to ALL.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Predisposição Genética para Doença/genética , Proteínas de Fusão Oncogênica/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas de Ligação a RNA/genética , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Criança , Epigenômica , Estudo de Associação Genômica Ampla , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Fatores de Risco , Transcriptoma
3.
Hum Mutat ; 40(9): 1557-1578, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31131967

RESUMO

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Biologia Computacional/métodos , Mutação de Sentido Incorreto , Neoplasias/diagnóstico , Processamento Alternativo , Detecção Precoce de Câncer , Feminino , Predisposição Genética para Doença , Humanos , Funções Verossimilhança , Masculino , Herança Multifatorial , Neoplasias/genética
4.
Front Physiol ; 10: 134, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30858804

RESUMO

Joubert syndrome (JS) is a congenital autosomal-recessive or-in rare cases-X-linked inherited disease. The diagnostic hallmark of the so-called molar tooth sign describes the morphological manifestation of the mid- and hind-brain in axial brain scans. Affected individuals show delayed development, intellectual disability, ataxia, hyperpnea, sleep apnea, abnormal eye, and tongue movements as well as hypotonia. At the cellular level, JS is associated with the compromised biogenesis of sensory cilia, which identifies JS as a member of the large group of ciliopathies. Here we report on the identification of novel compound heterozygous variants (p.Y503C and p.Q485*) in the centrosomal gene PIBF1 in a patient with JS via trio whole exome sequencing. We have studied the underlying disease mechanism in the frog Xenopus, which offers fast assessment of cilia functions in a number of embryological contexts. Morpholino oligomer (MO) mediated knockdown of the orthologous Xenopus pibf1 gene resulted in defective mucociliary clearance in the larval epidermis, due to reduced cilia numbers and motility on multiciliated cells. To functionally assess patient alleles, mutations were analyzed in the larval skin: the p.Q485* nonsense mutation resulted in a disturbed localization of PIBF1 to the ciliary base. This mutant failed to rescue the ciliation phenotype following knockdown of endogenous pibf1. In contrast, the missense variant p.Y503C resulted in attenuated rescue capacity compared to the wild type allele. Based on these results, we conclude that in the case of this patient, JS is the result of a pathogenic combination of an amorphic and a hypomorphic PIBF1 allele. Our study underscores the versatility of the Xenopus model to study ciliopathies such as JS in a rapid and cost-effective manner, which should render this animal model attractive for future studies of human ciliopathies.

5.
Nat Commun ; 10(1): 419, 2019 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-30664635

RESUMO

The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.

6.
Nat Commun ; 9(1): 1340, 2018 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-29632299

RESUMO

Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10-9, odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 × 10-8, OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Criança , Pré-Escolar , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Glicosiltransferases/genética , Antígenos HLA/genética , Humanos , Masculino , Proteínas de Fusão Oncogênica/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Prognóstico , Fatores de Risco
7.
Int J Cancer ; 143(6): 1416-1425, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-29659014

RESUMO

To evaluate the role of constitutive epigenetic changes in normal body cells of BRCA1/BRCA2-mutation negative patients, we have developed a deep bisulfite sequencing assay targeting the promoter regions of 8 tumor suppressor (TS) genes (BRCA1, BRCA2, RAD51C, ATM, PTEN, TP53, MLH1, RB1) and the estrogene receptor gene (ESR1), which plays a role in tumor progression. We analyzed blood samples of two breast cancer (BC) cohorts with early onset (EO) and high risk (HR) for a heterozygous mutation, respectively, along with age-matched controls. Methylation analysis of up to 50,000 individual DNA molecules per gene and sample allowed quantification of epimutations (alleles with >50% methylated CpGs), which are associated with epigenetic silencing. Compared to ESR1, which is representative for an average promoter, TS genes were characterized by a very low (< 1%) average methylation level and a very low mean epimutation rate (EMR; < 0.0001% to 0.1%). With exception of BRCA1, which showed an increased EMR in BC (0.31% vs. 0.06%), there was no significant difference between patients and controls. One of 36 HR BC patients exhibited a dramatically increased EMR (14.7%) in BRCA1, consistent with a disease-causing epimutation. Approximately one third (15 of 44) EO BC patients exhibited increased rates of single CpG methylation errors in multiple TS genes. Both EO and HR BC patients exhibited global underexpression of blood TS genes. We propose that epigenetic abnormalities in normal body cells are indicative of disturbed mechanisms for maintaining low methylation and appropriate expression levels and may be associated with an increased BC risk.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Ilhas de CpG/genética , Metilação de DNA , Epigênese Genética , Mutação , Proteínas Supressoras de Tumor/genética , Adulto , Alelos , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Prognóstico , Regiões Promotoras Genéticas , Fatores de Risco
8.
BMC Cancer ; 18(1): 265, 2018 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-29514593

RESUMO

BACKGROUND: There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group. METHODS: The study comprised 802 women (median age 40 years, range 19-76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation. RESULTS: A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20-29 years compared to 6.9% in the age group 60-69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50-2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years. CONCLUSIONS: Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais/genética , Testes Genéticos , Mutação em Linhagem Germinativa , Neoplasias de Mama Triplo Negativas/genética , Neoplasias Unilaterais da Mama/genética , Adulto , Idoso , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Pessoa de Meia-Idade , Prevalência , Prognóstico , Neoplasias de Mama Triplo Negativas/epidemiologia , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias Unilaterais da Mama/epidemiologia , Neoplasias Unilaterais da Mama/patologia , Adulto Jovem
9.
J Clin Oncol ; 36(12): 1240-1249, 2018 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-29498923

RESUMO

Purpose Somatic deletions that affect the lymphoid transcription factor-coding gene IKZF1 have previously been reported as independently associated with a poor prognosis in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). We have now refined the prognostic strength of IKZF1 deletions by analyzing the effect of co-occurring deletions. Patients and Methods The analysis involved 991 patients with BCP ALL treated in the Associazione Italiana Ematologia ed Oncologia Pediatrica-Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 trial with complete information for copy number alterations of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, Xp22.33/Yp11.31 (PAR1 region; CRLF2, CSF2RA, and IL3RA), and ERG; replication of findings involved 417 patients from the same trial. Results IKZF1 deletions that co-occurred with deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion conferred the worst outcome and, consequently, were grouped as IKZF1plus. The IKZF1plus group comprised 6% of patients with BCP ALL, with a 5-year event-free survival of 53 ± 6% compared with 79 ± 5% in patients with IKZF1 deletion who did not fulfill the IKZF1plus definition and 87 ± 1% in patients who lacked an IKZF1 deletion ( P ≤ .001). Respective 5-year cumulative relapse incidence rates were 44 ± 6%, 11 ± 4%, and 10 ± 1% ( P ≤ .001). Results were confirmed in the replication cohort, and multivariable analyses demonstrated independence of IKZF1plus. The IKZF1plus prognostic effect differed dramatically in analyses stratified by minimal residual disease (MRD) levels after induction treatment: 5-year event-free survival for MRD standard-risk IKZF1plus patients was 94 ± 5% versus 40 ± 10% in MRD intermediate- and 30 ± 14% in high-risk IKZF1plus patients ( P ≤ .001). Corresponding 5-year cumulative incidence of relapse rates were 6 ± 6%, 60 ± 10%, and 60 ± 17% ( P ≤ .001). Conclusion IKZF1plus describes a new MRD-dependent very-poor prognostic profile in BCP ALL. Because current AIEOP-BFM treatment is largely ineffective for MRD-positive IKZF1plus patients, new experimental treatment approaches will be evaluated in our upcoming trial AIEOP-BFM ALL 2017.


Assuntos
Deleção de Genes , Fator de Transcrição Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Criança , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Humanos , Masculino , Neoplasia Residual/genética , Neoplasia Residual/patologia , Fator de Transcrição PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Prognóstico , Receptor PAR-1/genética
10.
J Clin Oncol ; 36(3): 244-253, 2018 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-29148893

RESUMO

Purpose Delayed intensification (DI) is an integral part of treatment of childhood acute lymphoblastic leukemia (ALL), but it is associated with relevant toxicity. Therefore, standard-risk patients of trial AIEOP-BFM ALL 2000 (Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With ALL) were investigated with the specific aim to reduce treatment intensity. Patients and Methods Between July 2000 and July 2006, 1,164 patients (1 to 17 years of age) with standard-risk ALL (defined as the absence of high-risk cytogenetics and undetectable minimal residual disease on days 33 and 78) were randomly assigned to either experimental reduced-intensity DI (protocol III; P-III) or standard DI (protocol II; P-II). Cumulative drug doses of P-III were reduced by 30% for dexamethasone and 50% for vincristine, doxorubicin, and cyclophosphamide, which shortened the treatment duration from 49 to 29 days. The study aimed at noninferiority of reduced-intensity P-III; analyses were performed according to treatment given. Results For P-III and P-II, respectively, the 8-year rate of disease-free survival (± SE) was 89.2 ± 1.3% and 92.3 ± 1.2% ( P = .04); cumulative incidence of relapse, 8.7 ± 1.2% and 6.4 ± 1.1% ( P = .09); and overall survival, 96.1 ± 0.8% and 98.0 ± 0.6% ( P = .06). Patients with ETV6-RUNX1-positive ALL and patients 1 to 6 years of age performed equally well in both arms. The incidence of death during remission was comparable, which indicates equivalent toxicity. The 8-year cumulative incidence rate of secondary malignancies was 1.3 ± 0.5% and 0.6 ± 0.4% for P-III and P-II, respectively ( P = .37). Conclusion Although the criteria used for the standard-risk definition in this trial identified patients with exceptionally good prognosis, reduction of chemotherapy was not successful mainly because of an increased rate of relapse. The data suggest that treatment reduction is feasible in specific subgroups, which underlines the biologic heterogeneity of this cohort selected according to treatment response.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Doxorrubicina/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Prednisona/administração & dosagem , Vincristina/administração & dosagem , Adolescente , Fatores Etários , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Ciclofosfamida/efeitos adversos , Dexametasona/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Doxorrubicina/efeitos adversos , Europa (Continente) , Feminino , Humanos , Lactente , Masculino , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prednisona/efeitos adversos , Recidiva , Medição de Risco , Fatores de Risco , Fatores de Tempo , Vincristina/efeitos adversos
11.
JNCI Cancer Spectr ; 2(4): pky069, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31360884

RESUMO

Background: The aim of this study was to assess whether minimal residual disease (MRD) at the end of induction front-line treatment can serve as a surrogate endpoint for event-free survival (EFS) in childhood B-lineage acute lymphoblastic leukemia. Methods: The analysis was based on individual data of 4830 patients from two large phase III trials that asked a randomized question on the effect of different corticosteroids (dexamethasone vs prednisone) during induction chemotherapy on EFS. The association between MRD classified in three ordered categories [negative = 0, low positive = (>0 and <5 × 10-4), and positive = (≥5 × 10-4)] and EFS at the individual and trial levels was evaluated with the meta-analytic approach based on the Plackett copula model. Centers within trial were grouped according to geographical area, and a total of 28 units were identified for the analysis. Results: MRD at the end of induction was a poor surrogate for treatment effect on EFS at the trial level, with R trial 2 = 0.09 (95% confidence interval [CI] = 0.00 to 0.29), whereas at the individual level it was strongly associated with EFS, with an odds ratio of 3.90 (95% CI = 3.35 to 4.44) of failure for patients with higher compared with lower MRD levels. Additional sensitivity and relevant subgroup analyses confirmed these findings at both trial- and patient-level association. Conclusions: Although MRD is a robust biomarker highly predictive of outcome for individual patients, clinicians and regulatory bodies should be cautious in using early MRD response in the context of complex multiagent acute lymphoblastic leukemia therapy as an early surrogate endpoint to predict the effect of a randomized treatment intervention on long-term EFS.

12.
Mol Genet Metab ; 121(4): 297-307, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28688840

RESUMO

Whole exome sequencing (WES) is well established in research and is now being introduced into clinically indicated diagnostics (so-called clinical exomes). We evaluated the diagnostic yield and clinical implications of WES in 72 patients from 60 families with undiagnosed neurodevelopmental disorders (NDD), neurometabolic disorders, and dystonias. Pathogenic or likely pathogenic variants leading to a molecular diagnosis could be identified in 21 of the 60 families (overall 35%, in 36% of patients with NDD, in 43% of patients with neurometabolic disorders, in 25% of patients with dystonias). In one family two coexisting autosomal recessive diseases caused by homozygous pathogenic variants in two different genes were diagnosed. In another family, a homozygous frameshift variant in STRADA was found to cause a severe NDD with early onset epilepsy, brain anomalies, hypotonia, heart defect, nephrocalcinosis, macrocephaly and distinctive facies so far designated as PMSE (polyhydramnios, megalencephaly, symptomatic epilepsy) syndrome. In 7 of the 21 families with a molecular diagnosis the pathogenic variants were only identified by clinical follow-up, manual reevaluation of the literature, a change of filter setting, and/or reconsideration of inheritance pattern. Most importantly, clinical implications included management changes in 8 cases and impact on family planning in 20 families with a molecular diagnosis. This study shows that reevaluation and follow-up can improve the diagnostic rate and that WES results have important implications on medical management and family planning. Furthermore, we could confirm STRADA as a gene associated with syndromic ID but find it questionable if the current designation as PMSE depicts the most important clinical features.


Assuntos
Exoma , Técnicas de Diagnóstico Molecular/métodos , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Serviços de Planejamento Familiar , Feminino , Predisposição Genética para Doença , Homozigoto , Humanos , Masculino , Transtornos do Neurodesenvolvimento/fisiopatologia , Linhagem , Gravidez , Análise de Sequência de DNA , Sequenciamento Completo do Exoma
13.
Am J Med Genet A ; 173(7): 1878-1886, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28489334

RESUMO

Neurodegeneration with brain iron accumulation (NBIA) is a group of neurodegenerative disorders characterized by iron accumulation in the basal ganglia. Recently, mutations in CoA synthase (COASY) have been identified as a cause of a novel NBIA subtype (COASY Protein-Associated Neurodegeneration, CoPAN) in two patients with dystonic paraparesis, parkinsonian features, cognitive impairment, behavior abnormalities, and axonal neuropathy. COASY encodes an enzyme required for Coenzyme A (CoA) biosynthesis. Using whole exome sequencing (WES) we identified compound heterozygous COASY mutations in two siblings with intellectual disability, ataxic gait, progressive spasticity, and obsessive-compulsive behavior. The "eye-of-the tiger-sign," a characteristic hypointense spot within the hyperintense globi pallidi on MRI found in the most common subtype of NBIA (Pantothenate Kinase-Associated Neurodegeneration, PKAN), was not present. Instead, bilateral hyperintensity and swelling of caudate nucleus, putamen, and thalamus were found. In addition, our patients showed a small corpus callosum and frontotemporal and parietal white matter changes, expanding the brain phenotype of patients with CoPAN. Metabolic investigations showed increased free carnitine and decreased acylcarnitines in the patients dried blood samples. Carnitine palmitoyl transferase 1 (CPT1) deficiency was excluded by further enzymatic and metabolic investigations. As CoA and its derivate Acetyl-CoA play an essential role in fatty acid metabolism, we assume that abnormal acylcarnitine profiles are a result of the COASY mutations. This report not only illustrates that WES is a powerful tool to elucidate the etiology of rare genetic diseases, but also identifies unique neuroimaging and metabolic findings that may be key features for an early diagnosis of CoPAN.

14.
Carcinogenesis ; 38(3): 312-320, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28426874

RESUMO

Breast cancer (BC) is the leading cancer in women worldwide. Changes in DNA methylation in peripheral blood could be associated with malignant diseases. Making use of screening results by llumina 27K Methylation Assay, we validated demethylation of five CpG sites of S100P gene in blood cell DNA of BC patients by three independent retrospective studies with subjects from different centers (Validation I: 235 familial BC case and 206 controls, odds ratio per -1% methylation > 1.03, and P < 6.00 × 10-8 for all five CpG sites; Validation II: 189 sporadic BC case and 189 controls, odds ratio per -1% methylation > 1.03, P < 8.0 × 10-5 for four CpG sites; Validation III: 156 sporadic BC case and 151 controls, odds ratio per -1% methylation > 1.03, P < 6.0 × 10-4 for four CpG sites). In addition, the blood-based S100P methylation pattern was similar among BC patients with differential clinical characteristics regardless of stage, receptor status and menopause status. The observed BC-associated decreased S100P methylation in blood mainly originates from the leucocytes subpopulations but not B cells. The methylation levels of most S100P CpG sites were inversely correlated with the expression of S100P in leucocytes (P < 1.2 × 10-4) and in tissue (P < 1.1 × 10-4). This study reveals significant association between blood-based decreased S100P methylation and BC, and provides another proof for the application of altered DNA methylation signatures from blood cells as potential markers for the detection of BC, especially for the early stage.


Assuntos
Neoplasias da Mama/genética , Proteínas de Ligação ao Cálcio/genética , Metilação de DNA/genética , Predisposição Genética para Doença , Proteínas de Neoplasias/genética , Adulto , Idoso , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Proteínas de Ligação ao Cálcio/sangue , Ilhas de CpG/genética , Feminino , Estudos de Associação Genética , Humanos , Pessoa de Meia-Idade , Proteínas de Neoplasias/sangue
15.
Am J Med Genet A ; 173(5): 1369-1373, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28371085

RESUMO

Recently, de novo heterozygous variants in DDX3X have been reported in about 1.5% of 2659 females with previously unexplained intellectual disability (ID). We report on the identification of DDX3X variants in two unrelated girls with clinical features of Toriello-Carey Syndrome (T-CS). In patient 1, the recurrent variant c.1703C>T; p.(P568L) was identified when reconsidering X-linked de novo heterozygous variants in exome sequencing data. In patient 2, the DDX3X variant c.1600C>G; p.(R534G) was also detected by exome sequencing. Based on these data, de novo heterozygous DDX3X variants should be considered not only in females with unexplained ID, but also in individuals with a clinical diagnosis of T-CS.


Assuntos
Agenesia do Corpo Caloso/genética , Anormalidades Craniofaciais/genética , RNA Helicases DEAD-box/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Deformidades Congênitas dos Membros/genética , Síndrome de Pierre Robin/genética , Anormalidades Urogenitais/genética , Agenesia do Corpo Caloso/diagnóstico , Agenesia do Corpo Caloso/fisiopatologia , Criança , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/fisiopatologia , Exoma/genética , Feminino , Genes Ligados ao Cromossomo X , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/fisiopatologia , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/fisiopatologia , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/fisiopatologia , Mutação , Fenótipo , Síndrome de Pierre Robin/diagnóstico , Síndrome de Pierre Robin/fisiopatologia , Anormalidades Urogenitais/diagnóstico , Anormalidades Urogenitais/fisiopatologia
16.
Oncotarget ; 7(39): 64191-64202, 2016 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-27577081

RESUMO

DNA methylation changes in peripheral blood DNA have been shown to be associated with solid tumors. We sought to identify methylation alterations in whole blood DNA that are associated with breast cancer (BC). Epigenome-wide DNA methylation profiling on blood DNA from BC cases and healthy controls was performed by applying Infinium HumanMethylation450K BeadChips. Promising CpG sites were selected and validated in three independent larger sample cohorts via MassARRAY EpiTyper assays. CpG sites located in three genes (cg06418238 in RPTOR, cg00736299 in MGRN1 and cg27466532 in RAPSN), which showed significant hypomethylation in BC patients compared to healthy controls in the discovery cohort (p < 1.00 x 10-6) were selected and successfully validated in three independent cohorts (validation I, n =211; validation II, n=378; validation III, n=520). The observed methylation differences are likely not cell-type specific, as the differences were only seen in whole blood, but not in specific sub cell-types of leucocytes. Moreover, we observed in quartile analysis that women in the lower methylation quartiles of these three loci had higher ORs than women in the higher quartiles. The combined AUC of three loci was 0.79 (95%CI 0.73-0.85) in validation cohort I, and was 0.60 (95%CI 0.54-0.66) and 0.62 (95%CI 0.57-0.67) in validation cohort II and III, respectively. Our study suggests that hypomethylation of CpG sites in RPTOR, MGRN1 and RAPSN in blood is associated with BC and might serve as blood-based marker supplements for BC if these could be verified in prospective studies.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , DNA Tumoral Circulante/genética , Metilação de DNA , Epigênese Genética , Perfilação da Expressão Gênica/métodos , Proteínas Musculares/genética , Análise de Sequência com Séries de Oligonucleotídeos , Proteína Regulatória Associada a mTOR/genética , Ubiquitina-Proteína Ligases/genética , Adulto , Idoso , Área Sob a Curva , Biomarcadores Tumorais/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , DNA Tumoral Circulante/sangue , Ilhas de CpG , Feminino , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Proteínas Musculares/sangue , Razão de Chances , Valor Preditivo dos Testes , Curva ROC , Proteína Regulatória Associada a mTOR/sangue , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Risco , Ubiquitina-Proteína Ligases/sangue
17.
Eur J Cancer ; 65: 91-101, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27479119

RESUMO

The 'Individualized Therapy for Relapsed Malignancies in Childhood' (INFORM) precision medicine study is a nationwide German program for children with high-risk relapsed/refractory malignancies, which aims to identify therapeutic targets on an individualised basis. In a pilot phase, reported here, we developed the logistical and analytical pipelines necessary for rapid and comprehensive molecular profiling in a clinical setting. Fifty-seven patients from 20 centers were prospectively recruited. Malignancies investigated included sarcomas (n = 25), brain tumours (n = 23), and others (n = 9). Whole-exome, low-coverage whole-genome, and RNA sequencing were complemented with methylation and expression microarray analyses. Alterations were assessed for potential targetability according to a customised prioritisation algorithm and subsequently discussed in an interdisciplinary molecular tumour board. Next-generation sequencing data were generated for 52 patients, with the full analysis possible in 46 of 52. Turnaround time from sample receipt until first report averaged 28 d. Twenty-six patients (50%) harbored a potentially druggable alteration with a prioritisation score of 'intermediate' or higher (level 4 of 7). Common targets included receptor tyrosine kinases, phosphoinositide 3-kinase-mammalian target of rapamycin pathway, mitogen-activated protein kinase pathway, and cell cycle control. Ten patients received a targeted therapy based on these findings, with responses observed in some previously treatment-refractory tumours. Comparative primary relapse analysis revealed substantial tumour evolution as well as one case of unsuspected secondary malignancy, highlighting the importance of re-biopsy at relapse. This study demonstrates the feasibility of comprehensive, real-time molecular profiling for high-risk paediatric cancer patients. This extended proof-of-concept, with examples of treatment consequences, expands upon previous personalised oncology endeavors, and presents a model with considerable interest and practical relevance in the burgeoning era of personalised medicine.


Assuntos
Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Técnicas de Diagnóstico Molecular , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Medicina de Precisão/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Neoplasias/genética , Projetos Piloto , Adulto Jovem
18.
Am J Med Genet A ; 170(6): 1502-9, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27016154

RESUMO

Intellectual disability (ID) with cerebellar ataxia comprises a genetically heterogeneous group of neurodevelopmental disorders. We identified a homozygous frameshift mutation in CWF19L1 (c.467delC; p.(P156Hfs*33)) by a combination of linkage analysis and Whole Exome Sequencing in a consanguineous Turkish family with a 9-year-old boy affected by early onset cerebellar ataxia and mild ID. Serial MRI showed mildly progressive cerebellar atrophy. Absent C19L1 protein expression in lymphoblastoid cell lines strongly suggested that c.467delC is a disease-causing alteration. One further pregnancy of the mother had been terminated at 22 weeks of gestation because of a small cerebellum and agenesis of corpus callosum. The homozygous CWF19L1 variant was also present in the fetus. Postmortem examination of the fetus in addition showed unilateral hexadactyly and vertebral malformations. These features have not been reported and may represent an expansion of the CWF19L1-related phenotypic spectrum, but could also be due to another, possibly autosomal recessive disorder. The exact function of the evolutionarily highly conserved C19L1 protein is unknown. So far, homozygous or compound heterozygous mutations in CWF19L1 have been identified in two Turkish siblings and a Dutch girl, respectively, affected by cerebellar ataxia and ID. A zebrafish model showed that CWF19L1 loss-of-function mutations result in abnormal cerebellar morphology and movement disorders. Our report corroborates that loss-of-function mutations in CWF19Ll lead to early onset cerebellar ataxia and (progressive) cerebellar atrophy. © 2016 Wiley Periodicals, Inc.


Assuntos
Proteínas de Ciclo Celular/genética , Cerebelo/anormalidades , Exoma , Sequenciamento de Nucleotídeos em Larga Escala , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Mutação , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Encéfalo/anormalidades , Criança , Hibridização Genômica Comparativa , Consanguinidade , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Estudos de Associação Genética , Ligação Genética , Humanos , Imagem por Ressonância Magnética , Masculino , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Radiografia
19.
Blood ; 127(17): 2101-12, 2016 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-26888258

RESUMO

Induction therapy for childhood acute lymphoblastic leukemia (ALL) traditionally includes prednisone; yet, dexamethasone may have higher antileukemic potency, leading to fewer relapses and improved survival. After a 7-day prednisone prephase, 3720 patients enrolled on trial Associazione Italiana di Ematologia e Oncologia Pediatrica and Berlin-Frankfurt-Münster (AIEOP-BFM) ALL 2000 were randomly selected to receive either dexamethasone (10 mg/m(2) per day) or prednisone (60 mg/m(2) per day) for 3 weeks plus tapering in induction. The 5-year cumulative incidence of relapse (± standard error) was 10.8 ± 0.7% in the dexamethasone and 15.6 ± 0.8% in the prednisone group (P < .0001), showing the largest effect on extramedullary relapses. The benefit of dexamethasone was partially counterbalanced by a significantly higher induction-related death rate (2.5% vs 0.9%, P = .00013), resulting in 5-year event-free survival rates of 83.9 ± 0.9% for dexamethasone and 80.8 ± 0.9% for prednisone (P = .024). No difference was seen in 5-year overall survival (OS) in the total cohort (dexamethasone, 90.3 ± 0.7%; prednisone, 90.5 ± 0.7%). Retrospective analyses of predefined subgroups revealed a significant survival benefit from dexamethasone only for patients with T-cell ALL and good response to the prednisone prephase (prednisone good-response [PGR]) (dexamethasone, 91.4 ± 2.4%; prednisone, 82.6 ± 3.2%; P = .036). In patients with precursor B-cell ALL and PGR, survival after relapse was found to be significantly worse if patients were previously assigned to the dexamethasone arm. We conclude that, for patients with PGR in the large subgroup of precursor B-cell ALL, dexamethasone especially reduced the incidence of better salvageable relapses, resulting in inferior survival after relapse. This explains the lack of benefit from dexamethasone in overall survival that we observed in the total cohort except in the subset of T-cell ALL patients with PGR. This trial was registered at www.clinicaltrials.gov (BFM: NCT00430118, AIEOP: NCT00613457).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Terapia Combinada , Irradiação Craniana , Dexametasona/administração & dosagem , Dexametasona/farmacocinética , Intervalo Livre de Doença , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Metotrexato/administração & dosagem , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Prednisona/administração & dosagem , Modelos de Riscos Proporcionais , Indução de Remissão , Resultado do Tratamento
20.
Br J Haematol ; 173(5): 742-8, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26913693

RESUMO

Minimal residual disease (MRD) at the end of induction therapy is important for risk stratification of acute lymphoblastic leukaemia (ALL), but bone marrow (BM) aspiration is often postponed or must be repeated to fulfil qualitative and quantitative criteria for morphological assessment of haematological remission and/or MRD analysis. The impact of BM aspiration delay on measured MRD levels and resulting risk stratification is currently unknown. We analysed paired MRD data of 289 paediatric ALL patients requiring a repeat BM aspiration. MRD levels differed in 108 patients (37%) with a decrease in the majority (85/108). This would have resulted in different risk group allocation in 64 of 289 patients (23%) when applying the ALL-Berlin-Frankfurt-Münster 2000 criteria. MRD change was associated with the duration of delay; 40% of patients with delay ≥7 days had a shift to lower MRD levels compared to only 18% after a shorter delay. Patients MRD-positive at the original but MRD-negative at the repeat BM aspiration (n = 50) had a worse 5-year event-free survival than those already negative at first aspiration (n = 115) (86 ± 5% vs. 94 ± 2%; P = 0·024). We conclude that BM aspirations should be pursued as scheduled in the protocol because delayed MRD sampling at end of induction may result in false-low MRD load and distort MRD-based risk assessment.


Assuntos
Exame de Medula Óssea/métodos , Erros de Diagnóstico/prevenção & controle , Neoplasia Residual/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Adolescente , Biópsia por Agulha Fina , Criança , Pré-Escolar , Diagnóstico Tardio , Feminino , Humanos , Lactente , Masculino , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Indução de Remissão , Medição de Risco , Fatores de Tempo , Resultado do Tratamento
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