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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.
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
3.
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
4.
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
5.
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
6.
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
7.
Hum Mol Genet ; 24(18): 5345-55, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26130695

RESUMO

Numerous genetic factors that influence breast cancer risk are known. However, approximately two-thirds of the overall familial risk remain unexplained. To determine whether some of the missing heritability is due to rare variants conferring high to moderate risk, we tested for an association between the c.5791C>T nonsense mutation (p.Arg1931*; rs144567652) in exon 22 of FANCM gene and breast cancer. An analysis of genotyping data from 8635 familial breast cancer cases and 6625 controls from different countries yielded an association between the c.5791C>T mutation and breast cancer risk [odds ratio (OR) = 3.93 (95% confidence interval (CI) = 1.28-12.11; P = 0.017)]. Moreover, we performed two meta-analyses of studies from countries with carriers in both cases and controls and of all available data. These analyses showed breast cancer associations with OR = 3.67 (95% CI = 1.04-12.87; P = 0.043) and OR = 3.33 (95% CI = 1.09-13.62; P = 0.032), respectively. Based on information theory-based prediction, we established that the mutation caused an out-of-frame deletion of exon 22, due to the creation of a binding site for the pre-mRNA processing protein hnRNP A1. Furthermore, genetic complementation analyses showed that the mutation influenced the DNA repair activity of the FANCM protein. In summary, we provide evidence for the first time showing that the common p.Arg1931* loss-of-function variant in FANCM is a risk factor for familial breast cancer.


Assuntos
Processamento Alternativo , Códon sem Sentido , DNA Helicases/genética , Reparo do DNA , Éxons , Adulto , Idade de Início , Alelos , Sítios de Ligação , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudos de Casos e Controles , DNA Helicases/metabolismo , Análise Mutacional de DNA , Feminino , Expressão Gênica , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Ribonucleoproteína Nuclear Heterogênea A1 , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Humanos , Metanálise como Assunto , Pessoa de Meia-Idade , Motivos de Nucleotídeos , Matrizes de Pontuação de Posição Específica , Ligação Proteica , Fatores de Risco , Adulto Jovem
8.
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 do Exoma
9.
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.

10.
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
11.
Hum Mol Genet ; 23(3): 590-601, 2014 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-24045615

RESUMO

Acute lymphoblastic leukemia (ALL) accounts for ∼25% of pediatric malignancies. Of interest, the incidence of ALL is observed ∼20% higher in males relative to females. The mechanism behind the phenomenon of sex-specific differences is presently not understood. Employing genome-wide genetic aberration screening in 19 ALL samples, one of the most recurrent lesions identified was monoallelic deletion of the 5' region of SLX4IP. We characterized this deletion by conventional molecular genetic techniques and analyzed its interrelationships with biological and clinical characteristics using specimens and data from 993 pediatric patients enrolled into trial AIEOP-BFM ALL 2000. Deletion of SLX4IP was detected in ∼30% of patients. Breakpoints within SLX4IP were defined to recurrent positions and revealed junctions with typical characteristics of illegitimate V(D)J-mediated recombination. In initial and validation analyses, SLX4IP deletions were significantly associated with male gender and ETV6/RUNX1-rearranged ALL (both overall P < 0.0001). For mechanistic validation, a second recurrent deletion affecting TAL1 and caused by the same molecular mechanism was analyzed in 1149 T-cell ALL patients. Validating a differential role by sex of illegitimate V(D)J-mediated recombination at the TAL1 locus, 128 out of 1149 T-cell ALL samples bore a deletion and males were significantly more often affected (P = 0.002). The repeatedly detected association of SLX4IP deletion with male sex and the extension of the sex bias to deletion of the TAL1 locus suggest that differential illegitimate V(D)J-mediated recombination events at specific loci may contribute to the consistent observation of higher incidence rates of childhood ALL in boys compared with girls.


Assuntos
Proteínas de Transporte/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Recombinases/genética , Recombinação V(D)J , Adolescente , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Criança , Pré-Escolar , Estudos de Coortes , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Deleção de Genes , Humanos , Lactente , Masculino , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Proteína 1 de Leucemia Linfocítica Aguda de Células T , Variante 6 da Proteína do Fator de Translocação ETS
12.
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
13.
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 , Imageamento por Ressonância Magnética , Masculino , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Radiografia
14.
Int J Cancer ; 136(8): 1845-55, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25213452

RESUMO

Breast cancer (BC) is the leading cause of cancer-related mortality in women worldwide. Changes in DNA methylation in peripheral blood could be associated with malignancy at early stage. However, the BC-associated DNA methylation signatures in peripheral blood were largely unknown. Here, we performed a genome-wide methylation screening and identified a BC-associated differentially methylated CpG site cg27091787 in the hyaluronoglucosaminidase 2 gene (HYAL2) (discovery round with 72 BC case and 24 controls: p = 2.61 × 10(-9) adjusted for cell-type proportions). The substantially decreased methylation of cg27091787 in BC cases was confirmed in two validation rounds (first validation round with 338 BC case and 507 controls: p < 0.0001; second validation round with 189 BC case and 189 controls: p < 0.0001). In addition to cg27091787, the decreased methylation of a 650-bp CpG island shore of HYAL2 was also associated with increased risk of BC. Moreover, the expression and methylation of HYAL2 were inversely correlated with a p-value of 0.006. To note, the BC-associated decreased HYAL2 methylation was replicated in the T-cell fraction (p = 0.034). The cg27091787 methylation level enabled a powerful discrimination of early-stage BC cases (stages 0 and I) from healthy controls [area under curve (AUC) = 0.89], and was robust for the detection of BC in younger women as well (age < 50, AUC = 0.87). Our study reveals a strong association between decreased HYAL2 methylation in peripheral blood and BC, and provides a promising blood-based marker for the detection of early BC.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Moléculas de Adesão Celular/genética , Metilação de DNA/genética , Predisposição Genética para Doença/genética , Hialuronoglucosaminidase/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Neoplasias da Mama/sangue , Estudos de Casos e Controles , Moléculas de Adesão Celular/sangue , Ilhas de CpG/genética , Detecção Precoce de Câncer/métodos , Feminino , Proteínas Ligadas por GPI/sangue , Proteínas Ligadas por GPI/genética , Humanos , Hialuronoglucosaminidase/sangue , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Adulto Jovem
15.
Am J Hum Genet ; 90(4): 701-7, 2012 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-22424600

RESUMO

Kohlschütter-Tönz syndrome (KTS) is an autosomal-recessive disease characterized by the combination of epilepsy, psychomotor regression, and amelogenesis imperfecta. The molecular basis has not yet been elucidated. Here, we report that KTS is caused by mutations in ROGDI. Using a combination of autozygosity mapping and exome sequencing, we identified a homozygous frameshift deletion, c.229_230del (p.Leu77Alafs(∗)64), in ROGDI in two affected individuals from a consanguineous family. Molecular studies in two additional KTS-affected individuals from two unrelated Austrian and Swiss families revealed homozygosity for nonsense mutation c.286C>T (p.Gln96(∗)) and compound heterozygosity for the splice-site mutations c.531+5G>C and c.532-2A>T in ROGDI, respectively. The latter mutation was also found to be heterozygous in the mother of the Swiss affected individual in whom KTS was reported for the first time in 1974. ROGDI is highly expressed throughout the brain and other organs, but its function is largely unknown. Possible interactions with DISC1, a protein involved in diverse cytoskeletal functions, have been suggested. Our finding that ROGDI mutations cause KTS indicates that the protein product of this gene plays an important role in neuronal development as well as amelogenesis.


Assuntos
Amelogênese Imperfeita/genética , Demência/genética , Epilepsia/genética , Proteínas de Membrana/genética , Mutação , Proteínas Nucleares/genética , Sequência de Bases , Mapeamento Cromossômico , Exoma , Éxons , Feminino , Heterozigoto , Homozigoto , Humanos , Lactente , Masculino , Dados de Sequência Molecular
16.
Blood ; 122(19): 3298-307, 2013 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-23996088

RESUMO

Acute lymphoblastic leukemia (ALL) is the major pediatric cancer diagnosed in economically developed countries with B-cell precursor (BCP)-ALL, accounting for approximately 70% of ALL. Recent genome-wide association studies (GWAS) have provided the first unambiguous evidence for common inherited susceptibility to BCP-ALL, identifying susceptibility loci at 7p12.2, 9p21.3, 10q21.2, and 14q11.2. To identify additional BCP-ALL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1658 cases and 4723 controls, with validation in 1449 cases and 1488 controls. Combined analysis identified novel loci mapping to 10p12.2 (rs10828317, odds ratio [OR] = 1.23; P = 2.30 × 10(-9)) and 10p14 marked by rs3824662 (OR = 1.31; P = 8.62 × 10(-12)). The single nucleotide polymorphism rs10828317 is responsible for the N215S polymorphism in exon 7 of PIP4K2A, and rs3824662 localizes to intron 3 of the transcription factor and putative tumor suppressor gene GATA3. The rs10828317 association was shown to be specifically associated with hyperdiploid ALL, whereas the rs3824662-associated risk was confined to nonhyperdiploid non-TEL-AML1 + ALL. The risk allele of rs3824662 was correlated with older age at diagnosis (P < .001) and significantly worse event-free survivorship (P < .0001). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to BCP-ALL and the influence of constitutional genotype on disease development.


Assuntos
Cromossomos Humanos Par 10 , Fator de Transcrição GATA3/genética , Fenótipo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Fatores Etários , Alelos , Linfócitos B/metabolismo , Linfócitos B/patologia , Criança , Éxons , Feminino , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Análise de Sobrevida
17.
Breast Cancer Res Treat ; 145(2): 451-60, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24728577

RESUMO

Variants of uncertain clinical significance (VUS) in the high-penetrance breast cancer susceptibility genes BRCA1 and BRCA2 represent a major obstacle in genetic counseling of high-risk breast cancer families. We analyzed a missense VUS located in BRCA2 (p.Asn3124Ile; HGVS: BRCA2 c.9371A > T) present in seven independent high-risk breast cancer families that were counseled and genetically tested in South-West Germany. The VUS was identified by DNA sequencing. We analyzed co-occurrence with deleterious BRCA1/2 mutations, segregation, evolutionary conservation, in silico impact prediction, and prevalence in the general population. All carriers of the VUS suffered from breast or ovarian cancer. In two families, an additional high burden of other cancers such as pancreatic, prostate, and gastric cancers was reported, one further family included two cases of male breast cancer. The VUS did not co-occur with deleterious BRCA1/2 mutations and segregated in two affected individuals of one family. In contrast to the 7/1,347 (0,5 %) tested high-risk BC families without clearly pathogenic mutations in BRCA1/2, none of 3,126 healthy population controls sharing the same ethnic and geographical background were found to carry this VUS (p = 0.0002). In-silico prediction revealed strong evolutionary conservation of the asparagine residue, residing in the C-terminal oligonucleotide-binding-fold-3 region, and a most likely damaging impact of this exchange on the protein structure. The BRCA2 p.Asn3124Ile (BRCA2 c.9371A > T) variant is a rare mutation with a damaging effect on the BRCA2 protein that is strongly associated with familial breast and ovarian cancer risk, indicating its most likely pathogenic nature and clinical relevance.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Mutação , Substituição de Aminoácidos , Proteína BRCA1/genética , Proteína BRCA2/química , Neoplasias da Mama Masculina/genética , Estudos de Casos e Controles , Simulação por Computador , Feminino , Predisposição Genética para Doença , Alemanha , Humanos , Masculino , Mutação de Sentido Incorreto , Neoplasias Ovarianas/genética , Linhagem
18.
Blood ; 120(9): 1868-76, 2012 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-22442346

RESUMO

Quantification of minimal residual disease (MRD) by real-time PCR directed to TCR and Ig gene rearrangements allows a refined evaluation of response in acute lymphoblastic leukemia (ALL). The German Multicenter Study Group for Adult ALL prospectively evaluated molecular response after induction/consolidation chemotherapy according to standardized methods and terminology in patients with Philadelphia chromosome-negative ALL. The cytologic complete response (CR) rate was 89% after induction phases 1 and 2. At this time point the molecular CR rate was 70% in 580 patients with cytologic CR and evaluable MRD. Patients with molecular CR after consolidation had a significantly higher probability of continuous complete remission (CCR; 74% vs 35%; P < .0001) and of overall survival (80% vs 42%; P = .0001) compared with patients with molecular failure. Patients with molecular failure without stem cell transplantation (SCT) in first CR relapsed after a median time of 7.6 months; CCR and survival at 5 years only reached 12% and 33%, respectively. Quantitative MRD assessment identified patients with molecular failure as a new high-risk group. These patients display resistance to conventional drugs and are candidates for treatment with targeted, experimental drugs and allogeneic SCT. Molecular response was shown to be highly predictive for outcome and therefore constitutes a relevant study end point. The studies are registered at www.clinicaltrials.gov as NCT00199056 and NCT00198991.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Quimioterapia de Indução/métodos , Neoplasia Residual/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Terapia Combinada , Humanos , Pessoa de Meia-Idade , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Estudos Prospectivos , Indução de Remissão , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
19.
Blood ; 117(14): 3809-15, 2011 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-21310923

RESUMO

In multiple myeloma (MM) pathogenesis, hyperdiploidy and nonhyperdiploidy are recognized as 2 major cytogenetic pathways. Here, we assessed the role of hyperdiploidy in 426 patients with monoclonal plasma cell disorders, among them 246 patients with AL amyloidosis (AL), by interphase fluorescence in situ hybridization. Hyperdiploidy was defined by a well-established score requiring trisomies for at least 2 of the 3 chromosomes 5, 9, and 15. The hyperdiploidy frequency in AL was a mere 11% compared with 30% in monoclonal gammopathy of undetermined significance (P < .001) and 46% in AL with concomitant MM I (P < .001). Overall, hyperdiploidy was associated with an intact immunoglobulin, κ light chain restriction, higher age, and bone marrow plasmacytosis, but was unrelated to the organ involvement pattern in AL. Clustering of 6 major cytogenetic aberrations in AL by an oncogenetic tree model showed that hyperdiploidy and t(11;14) were almost mutually exclusive, whereas gain of 1q21 favored hyperdiploidy. Deletion 13q14 and secondary IgH translocations were equally distributed between ploidy groups. We conclude that the interphase fluorescence in situ hybridization-based hyperdiploidy score is also a feasible tool to delineate hyperdiploid patients in early-stage monoclonal gammopathies and that the cytogenetic pathogenetic concepts developed in MM are transferable to AL.


Assuntos
Amiloidose/genética , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 14 , Diploide , Gamopatia Monoclonal de Significância Indeterminada/genética , Translocação Genética/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Amiloidose/imunologia , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 14/genética , Estudos de Coortes , Feminino , Frequência do Gene , Humanos , Cadeias Leves de Imunoglobulina/genética , Masculino , Pessoa de Meia-Idade
20.
Blood ; 118(8): 2077-84, 2011 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-21719599

RESUMO

The prognostic value of MRD in large series of childhood T-ALL has not yet been established. Trial AIEOP-BFM-ALL 2000 introduced standardized quantitative assessment of MRD for stratification, based on immunoglobulin and TCR gene rearrangements as polymerase chain reaction targets: Patients were considered MRD standard risk (MRD-SR) if MRD was negative at day 33 (time point 1 [TP1]) and day 78 (TP2), analyzed by at least 2 sensitive markers; MRD intermediate risk (MRD-IR) if positive either at day 33 or 78 and < 10(-3) at day 78; and MRD high risk (MRD-HR) if ≥ 10(-3) at day 78. A total of 464 patients with T-ALL were stratified by MRD: 16% of them were MRD-SR, 63% MRD-IR, and 21% MRD-HR. Their 7-year event-free-survival (SE) was 91.1% (3.5%), 80.6% (2.3%), and 49.8% (5.1%) (P < .001), respectively. Negativity of MRD at TP1 was the most favorable prognostic factor. An excellent outcome was also obtained in 32% of patients turning MRD negative only at TP2, indicating that early (TP1) MRD levels were irrelevant if MRD at TP2 was negative (48% of all patients). MRD ≥ 10(-3) at TP2 constitutes the most important predictive factor for relapse in childhood T-ALL. The study is registered at http://www.clinicaltrials.gov; "Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With Acute Lymphoblastic Leukemia," protocol identification #NCT00430118 for BFM and #NCT00613457 for AIEOP.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras/classificação , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Rearranjo Gênico do Linfócito B , Rearranjo Gênico do Linfócito T , Humanos , Lactente , Masculino , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/imunologia , Prognóstico , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo
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