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1.
Anticancer Res ; 39(6): 2861-2869, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177124

RESUMO

BACKGROUND/AIM: PON1 gene has an executive role in antioxidant defense, protecting cells from genotoxic factors. Q192R and L55M PON1 polymorphisms reduce catalytic activity of the encoded protein. These polymorphisms were studied in 300 chronic lymphocytic leukemia (CLL) patients and 106 healthy donors. They were also associated with patients' cytogenetic findings, to investigate their possible implication in CLL pathogenesis. MATERIALS AND METHODS: SNP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Karyotypic analysis was also performed by chromosome G-banding analysis and fluorescence in situ hybridization. RESULTS: Genotypic and allelic distribution of Q192R polymorphism showed a statistically significant higher frequency of mutant genotypes and mutant alleles in patients compared to controls. The same observation was noted in patients with abnormal karyotypes and those carrying abn14q32 and del(6q). A statistically increased frequency for the mutant allele was also revealed in patients with del(11q). On the contrary, L55M polymorphism showed a similar distribution between patients and controls. CONCLUSION: Q192R polymorphism plays a role in CLL predisposition and the formation of specific chromosomal aberrations.


Assuntos
Arildialquilfosfatase/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 6/genética , Leucemia Linfocítica Crônica de Células B/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Aberrações Cromossômicas , Feminino , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Pessoa de Meia-Idade
3.
BMJ Case Rep ; 12(5)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31079043

RESUMO

Uniparental disomy (UPD) is a congenital disease characterised by the presence of two homologous chromosomes inherited from one parent in a diploid offspring. Maternal UPD of the chromosome 14 (UPD(14)mat, Temple syndrome) is a rare disorder with heterogeneous clinical presentation. Here, we report a case of UPD(14)mat with a small supernumerary marker chromosome in a 6-year-old baby girl, presenting endocrinological disorders and incomplete clinical presentation. She came to our attention because of precocious beginning of pubarche and normal stature. Most of Temple syndrome signs were lacking. Provocative tests diagnosed incomplete growth hormone (GH) response and confirmed precocious puberty. One year treatment with recombinant human GH and gonadotropin-releasing hormone (GnRH) agonists proved successful, increasing height and arresting puberty. We recommend provocative tests for GH in UPD(14)mat as a GH deficiency can be hidden by a concurrent precocious puberty. Concomitant human GH and GnRH analogue treatment can be pursued.


Assuntos
Hormônio do Crescimento Humano/uso terapêutico , Puberdade Precoce/tratamento farmacológico , Pamoato de Triptorrelina/uso terapêutico , Dissomia Uniparental/genética , Criança , Cromossomos Humanos Par 14/genética , Feminino , Humanos , Puberdade Precoce/etiologia
4.
Genome Med ; 11(1): 25, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31014393

RESUMO

BACKGROUND: Intrachromosomal triplications (TRP) can contribute to disease etiology via gene dosage effects, gene disruption, position effects, or fusion gene formation. Recently, post-zygotic de novo triplications adjacent to copy-number neutral genomic intervals with runs of homozygosity (ROH) have been shown to result in uniparental isodisomy (UPD). The genomic structure of these complex genomic rearrangements (CGRs) shows a consistent pattern of an inverted triplication flanked by duplications (DUP-TRP/INV-DUP) formed by an iterative DNA replisome template-switching mechanism during replicative repair of a single-ended, double-stranded DNA (seDNA), the ROH results from an interhomolog or nonsister chromatid template switch. It has been postulated that these CGRs may lead to genetic abnormalities in carriers due to dosage-sensitive genes mapping within the copy-number variant regions, homozygosity for alleles at a locus causing an autosomal recessive (AR) disease trait within the ROH region, or imprinting-associated diseases. METHODS: Here, we report a family wherein the affected subject carries a de novo 2.2-Mb TRP followed by 42.2 Mb of ROH and manifests clinical features overlapping with those observed in association with chromosome 14 maternal UPD (UPD(14)mat). UPD(14)mat can cause clinical phenotypic features enabling a diagnosis of Temple syndrome. This CGR was then molecularly characterized by high-density custom aCGH, genome-wide single-nucleotide polymorphism (SNP) and methylation arrays, exome sequencing (ES), and the Oxford Nanopore long-read sequencing technology. RESULTS: We confirmed the postulated DUP-TRP/INV-DUP structure by multiple orthogonal genomic technologies in the proband. The methylation status of known differentially methylated regions (DMRs) on chromosome 14 revealed that the subject shows the typical methylation pattern of UPD(14)mat. Consistent with these molecular findings, the clinical features overlap with those observed in Temple syndrome, including speech delay. CONCLUSIONS: These data provide experimental evidence that, in humans, triplication can lead to segmental UPD and imprinting disease. Importantly, genotype/phenotype analyses further reveal how a post-zygotically generated complex structural variant, resulting from a replication-based mutational mechanism, contributes to expanding the clinical phenotype of known genetic syndromes. Mechanistically, such events can distort transmission genetics resulting in homozygosity at a locus for which only one parent is a carrier as well as cause imprinting diseases.


Assuntos
Aberrações Cromossômicas , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 14/genética , Impressão Genômica , Transtornos Cromossômicos/patologia , Metilação de DNA , Replicação do DNA , Humanos , Masculino , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto Jovem
5.
J Cutan Pathol ; 46(7): 538-541, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30957249

RESUMO

Secondary cutaneous involvement by mantle cell lymphoma (MCL), an uncommon aggressive B-cell malignancy, predominantly involves the dermis, with few reports of pannicular involvement. Lymphocytic infiltration of subcutaneous tissue is associated with inflammatory panniculitides and certain T-cell lymphomas, primarily subcutaneous panniculitis-like T-Cell lymphoma (SPTCL), which is characterized by rimming of adipocytes by tumor cells. We report the case of a 69-year-old man with a history of systemic nodal MCL who presented with subcutaneous nodules on his lower extremities after receiving multi-agent chemotherapy. Biopsies showed a dense infiltrate of atypical, mitotically active, monomorphic, medium-sized lymphoid cells in the subcutaneous fat with prominent rimming of the adipocytes by the tumor cells. These features were not morphologically typical of MCL. Immunohistochemistry showed these cells to be CD20+, CD5+ B-cells with strong cyclin D1 expression; fluorescence in situ hybridization (FISH) analysis was positive for t(11;14)(q13;32), confirming the diagnosis of secondary cutaneous involvement of MCL. This represents an exceptional report of cutaneous MCL presenting clinically and histologically with a panniculitis-type pattern and adipocyte rimming, histomorphologically mimicking SPTCL. Noteworthy examples, such as this report, support the practice of utilizing clinical correlation, immunohistochemistry, and/or molecular cytogenetics to confirm the diagnosis of any case suspicious for cutaneous lymphoma.


Assuntos
Linfoma de Célula do Manto , Linfoma de Células T , Paniculite , Neoplasias Cutâneas , Idoso , Antígenos CD20/genética , Antígenos CD20/metabolismo , Linfócitos B/metabolismo , Linfócitos B/patologia , Antígenos CD5/genética , Antígenos CD5/metabolismo , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 11/metabolismo , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 14/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Diagnóstico Diferencial , Humanos , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Linfoma de Células T/diagnóstico , Linfoma de Células T/genética , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Masculino , Paniculite/diagnóstico , Paniculite/genética , Paniculite/metabolismo , Paniculite/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Translocação Genética
6.
Int J Hematol ; 109(5): 572-577, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30887274

RESUMO

Light-chain plasma cell myeloma (LC-PCM) is a PCM subtype in which only immunoglobulin light-chain is secreted. However, the absence of immunoglobulin heavy-chain (IGH) production in this condition has not been fully elucidated. To address this issue, we retrospectively analyzed patients at our center with LC-PCM and found a group who had only split signals of IGH gene derived from 14q32/IGH translocations by fluorescence in situ hybridization (FISH). Six patients were identified with only split signals of the IGH gene derived from 14q32/IGH translocations. Five of these patients were newly diagnosed, while one had IgG-λ PCM at presentation, which transformed to λ LC-PCM after treatment. The translocation partners were identified in four patients: two cases of (11;14)(q13;q32) and two cases of (4;14)(p16;q32). The development of LC-PCM appears to be explained by the application of allelic exclusion in these patients, such that 14q32/IGH translocation in one allele contributes to the pathogenesis of PCM and the subsequent loss of the other allele is responsible for the loss of IGH production. These findings suggest that a FISH pattern of IGH with "split and loss" may constitute a unique subgroup of LC-PCM.


Assuntos
Cromossomos Humanos Par 14/genética , Cadeias lambda de Imunoglobulina , Leucemia Plasmocitária/genética , Perda de Heterozigosidade , Translocação Genética , Idoso , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 4/genética , Feminino , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética
7.
Int J Hematol ; 110(2): 250-254, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30903564

RESUMO

Hereditary spherocytosis (HS) is a heterogeneous genetic disorder characterized by spherocytosis on peripheral blood smear with hemolytic anemia, accompanied by signs of hemolysis. Herein, we report a 5-month-old Korean girl with HS resulting from a de novo 271 Kb microdeletion of 14q23.3. She presented with hemolytic anemia and mild splenomegaly. Spherocytosis was seen on examination of peripheral blood. Eosin-5'-maleimide (EMA) test and flow cytometric osmotic fragility test were positive. She had no relevant family history of spherocytosis. No pathogenic single nucleotide variants or small insertions/deletions were detected in HS-associated genes. Array comparative genomic hybridization analysis revealed a 271 Kb deletion at chromosome 14q23.3, encompassing the SPTB, CHURC1, GPX2, RAB15, FNTB, and MAX genes. We found a deletion affecting 5' UTR, exon 1, and part of intron 1 of the SPTB gene using targeted next-generation sequencing (NGS) analysis, suggesting that NGS may be able to identify disease-causing copy number variations (CNVs), as well as small point mutations in HS patients. In addition, chromosomal microarray may be useful in defining combined deleted genes. Additional evaluations should thus be considered in the diagnosis of HS, especially when CNV is revealed as disease-causing abnormality.


Assuntos
Variações do Número de Cópias de DNA , Espectrina/genética , Esferocitose Hereditária/genética , Regiões 5' não Traduzidas , Pré-Escolar , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 14/ultraestrutura , Hibridização Genômica Comparativa , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deleção de Sequência , Esferocitose Hereditária/sangue , Esferocitose Hereditária/complicações , Esplenomegalia/etiologia
8.
Cells ; 8(2)2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30743997

RESUMO

Relapsing-remitting multiple sclerosis (RRMS) is the most prevalent course of multiple sclerosis. It is an autoimmune inflammatory disease of the central nervous system. To investigate the gender-specific involvement of microRNAs (miRNAs) in RRMS pathogenesis, we compared miRNA profiles in peripheral blood mononuclear cells separately in men and women (eight RRMS patients versus four healthy controls of each gender) using high-throughput sequencing. In contrast to women, six downregulated and 26 upregulated miRNAs (padj < 0.05) were identified in men with RRMS. Genes encoding upregulated miRNAs are co-localized in DLK1-DIO3 imprinted locus on human chromosome 14q32. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis was performed in independent groups of men (16 RRMS patients and 10 healthy controls) and women (20 RRMS patients and 10 healthy controls). Increased expression of miR-431, miR-127-3p, miR-379, miR-376c, miR-381, miR-410 and miR-656 was again demonstrated in male (padj < 0.05), but not in female RRMS patients. At the same time, the expression levels of these miRNAs were lower in healthy men than in healthy women, whereas in RRMS men they increased and reached or exceeded levels in RRMS women. In general, we demonstrated that expression levels of these miRNAs depend both on "health⁻disease" status and gender. Network-based enrichment analysis identified that receptor tyrosine kinases-activated pathways were enriched with products of genes targeted by miRNAs from DLK1-DIO3 locus. These results suggest the male-specific involvement of these miRNAs in RRMS pathogenesis via regulation of PI3K/Akt signaling.


Assuntos
Cromossomos Humanos Par 14/genética , Regulação da Expressão Gênica , Loci Gênicos , Impressão Genômica , MicroRNAs/metabolismo , Esclerose Múltipla/genética , Receptores Proteína Tirosina Quinases/metabolismo , Caracteres Sexuais , Proteínas de Ligação ao Cálcio , Feminino , Redes Reguladoras de Genes , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Iodeto Peroxidase/genética , Masculino , Proteínas de Membrana/genética , MicroRNAs/genética , Transdução de Sinais
9.
Int J Hematol ; 109(6): 731-736, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30680670

RESUMO

A 67-year-old female was referred to our hospital with a sternal fracture in March 2008. She received a diagnosis of multiple myeloma (MM) BJP-κ type (ISS stage III). G-banding karyotype revealed 46, XX, t(11;22)(q23.3;q11.2) (Hubacek, Gene 592:193-9, 2016), which was later confirmed to be congenital. After repeated rounds of chemotherapy with bortezomib and lenalidomide, she obtained a very good partial response in August 2014, and she was followed up with no treatment. However, she relapsed in February 2016. At that time, fluorescence in situ hybridization identified del(13q) and t(4;14)(p16;q32), which are associated with a poor prognosis. Furthermore, PCR analysis showed that the chromosome 11 breakpoint was at the APOA5/APOA4 locus at 11q23.3, which is associated with malignancy, and that the chromosome 22 breakpoint was at the SEPT5 intron 1 locus, which also plays a role in leukemogenesis through formation of a fusion gene with MLL. Although she was treated with three further lines of therapy, she died from disease progression in August 2017. Synergism between t(11;22) and t(4;14) may have induced the double-refractory phenotype to proteasome inhibitor and lenalidomide, at least during the chemorefractory phase. We present a biological analysis of this case and a review of the literature.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 11/genética , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Proteínas de Fusão Oncogênica/genética , Idoso , Bortezomib/uso terapêutico , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 4/genética , Progressão da Doença , Quimioterapia Combinada , Evolução Fatal , Feminino , Humanos , Lenalidomida/uso terapêutico
10.
J Hum Genet ; 64(4): 271-280, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30670789

RESUMO

A decade ago, we described novel de novo submicroscopic deletions of chromosome 14q11.2 in three children with developmental delay, cognitive impairment, and similar dysmorphic features, including widely-spaced eyes, short nose with flat nasal bridge, long philtrum, prominent Cupid's bow of the upper lip, full lower lip, and auricular anomalies. We suggested that this constituted a new multiple congenital anomaly-intellectual disability syndrome due to defects in CHD8 and/or SUPT16H. The three patients in our original cohort were between 2 years and 3 years of age at the time. Here we present a fourth patient and clinical updates on our previous patients. To document the longitudinal course more fully, we integrate published reports of other patients and describe genotype-phenotype correlations among them. Children with the disorder present with developmental delay, intellectual disability, and/or autism spectrum disorder in addition to characteristic facies. Gastrointestinal and sleep problems are notable. The identification of multiple patients with the same genetic defect and characteristic clinical phenotype, confirms our suggestion that this is a syndromic disorder caused by haploinsufficiency or heterozygous loss of function of CHD8.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 14/genética , Facies , Feminino , Haploinsuficiência/genética , Heterozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Megalencefalia/genética , Megalencefalia/fisiopatologia , Transtornos do Neurodesenvolvimento/patologia
11.
Jpn J Clin Oncol ; 49(2): 195-198, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30608548

RESUMO

According to fluorescent in situ hybridization, t(11;14) is the most common cytogenetic abnormality in amyloid light-chain (AL) amyloidosis, but its prevalence in patients with AL amyloidosis and concurrent multiple myeloma (MM) remains unknown. We aimed to examine the prevalence of t(11;14) and the differences in clinical characteristics of patients with t(11;14) who had AL amyloidosis with or without concurrent MM. We retrospectively analyzed 40 patients with AL amyloidosis between January 2008 and January 2018 at our institution. The prevalence of t(11;14) was significantly higher in patients with AL amyloidosis alone compared with those with concurrent MM (56.5% vs. 17.6%; P = 0.022). This study suggests that AL amyloidosis patients with concurrent MM have a lower prevalence of t(11;14) than those without MM and that the presence of t(11;14) may be associated with poor prognosis, irrespective of the presence or absence of MM.


Assuntos
Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 14/genética , Amiloidose de Cadeia Leve de Imunoglobulina/complicações , Amiloidose de Cadeia Leve de Imunoglobulina/genética , Mieloma Múltiplo/complicações , Mieloma Múltiplo/genética , Translocação Genética , Idoso , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Prevalência , Prognóstico , Estudos Retrospectivos
13.
J Formos Med Assoc ; 118(3): 739-742, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30616993

RESUMO

Paternal uniparental disomy 14 (UDP(14)pat) is a rare imprinting disorder with a set of unique neonatal clinical features documented, including craniofacial abnormalities, thoracic and abdominal wall defects, and polyhydraminos. To date, no studies focus on prenatal diagnosis of uniparental disomy have been published. We report a case of a fetus with abnormal ultrasound features at 18 weeks of gestation and normal karyotype result. Subsequent Single nucleotide polymorphism (SNP)-based Affymetrix 750K Microarray analysis revealed the complete loss of heterozygosity for chromosome 14, identifying a case of uniparental disomy. Postmortem examination of the aborted fetus at 21 weeks, coupled with further Affymetrix 750K microarray analysis on the parents, confirmed the diagnosis of parental uniparental disomy for chromosome 14.


Assuntos
Cromossomos Humanos Par 14/genética , Diagnóstico Pré-Natal/métodos , Dissomia Uniparental/diagnóstico , Dissomia Uniparental/genética , Adulto , Feminino , Humanos , Análise em Microsséries , Polimorfismo de Nucleotídeo Único , Gravidez , Ultrassonografia Pré-Natal
14.
Leukemia ; 33(3): 739-748, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30470837

RESUMO

Multiple myeloma (MM) is characterized by recurrent chromosomal translocations. T(4;14) MM overexpresses multiple myeloma SET domain-containing protein (MMSET). MMSET has three major isoforms: the full-length form MMSET II and the short isoforms REIIBP and MMSET I. Here we show that the short isoform MMSET I is an oncoprotein that promoted cell survival and tumorigenesis in vitro and in vivo. Gene expression array analysis indicated that MMSET I increased glyoxalase I (GLO1) expression. Chromatin immunoprecipitation (ChIP) coupled with qPCR indicated that MMSET I bound upstream of the GLO1 transcription start site. Ectopic overexpression of MMSET I or its mutants showed MMSET I depended on its C terminus to regulate GLO1 expression. GLO1 knockdown (KD) induced apoptosis and reduced colony formation. MMSET I or GLO1 KD reduced the levels of anti-apoptosis factors such as MCL1 and BCL2. Ectopic overexpression of GLO1 resulted in the significant rescue of KMS11 cells from MMSET I KD-induced apoptosis and glycolysis inhibition. This suggested that GLO1 may be of functional importance target downstream of MMSET I. Cumulatively, our study suggests that MMSET I is an oncoprotein and potential therapeutic target for t(4;14) MM.


Assuntos
Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 4/genética , Histona-Lisina N-Metiltransferase/genética , Lactoilglutationa Liase/genética , Mieloma Múltiplo/genética , Proteínas Oncogênicas/genética , Proteínas Repressoras/genética , Apoptose/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Imunoprecipitação da Cromatina/métodos , Regulação Neoplásica da Expressão Gênica/genética , Glicólise/genética , Humanos , Isoformas de Proteínas/genética , Translocação Genética/genética
16.
J Cutan Pathol ; 46(3): 182-189, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30511443

RESUMO

BACKGROUND: Primary cutaneous follicular center-cell lymphoma (PCFCL) is one of the most common types of cutaneous B-cell lymphoma. Differences in immunohistochemical expression of BCL2 and CD10 antigens along with the presence of t(14:18) translocation in neoplastic cells have been postulated as relevant clues in differentiating PCFCL from cutaneous lesions secondary to a systemic follicular lymphoma (SCFL). The aim of this study is to evaluate the significance and usefulness of these parameters in a large series of patients. METHODS: Patients with PCFCL and SCFL diagnosed at three university hospitals in Barcelona, from 2000 to 2015 were reviewed. Clinical, histopathological, immunophenotypical, genetic, and outcome parameters were analyzed. RESULTS: Eighty-one cases (59 PCFCL and 22 SCFL) were included. There were no significant differences between PCFCL and SCFL cases regarding clinical presentation, site of involvement, or predominant type of skin lesions. Most patients in both groups showed positivity for BCL2 and CD10, but strong expression of BCL2 and CD10 was associated with SCFL cases. Although more frequent in SCFL, a small proportion of PCFCL cases also showed the t(14:18) on FISH analysis. CONCLUSION: The intensity of BCL2 expression was found to be the single most valuable clue in differentiating PCFCL from SCFL cases on histopathological grounds.


Assuntos
Biomarcadores Tumorais/análise , Linfoma Folicular/diagnóstico , Neoplasias Cutâneas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 18/genética , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neprilisina/análise , Neprilisina/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Translocação Genética/genética , Adulto Jovem
17.
Am J Hematol ; 94(1): E35-E37, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30370955
18.
Leukemia ; 33(1): 1-14, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29977016

RESUMO

Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy. Genome-wide association studies have shown variation at 14q11.2 influences ALL risk. We sought to decipher causal variant(s) at 14q11.2 and the mechanism of tumorigenesis. We show rs2239630 G>A resides in the promoter of the CCAT enhancer-binding protein epsilon (CEBPE) gene. The rs2239630-A risk allele is associated with increased promotor activity and CEBPE expression. Depletion of CEBPE in ALL cells reduces cell growth, correspondingly CEBPE binds to the promoters of electron transport and energy generation genes. RNA-seq in CEBPE depleted cells demonstrates CEBPE regulates the expression of genes involved in B-cell development (IL7R), apoptosis (BCL2), and methotrexate resistance (RASS4L). CEBPE regulated genes significantly overlapped in CEBPE depleted cells, ALL blasts and IGH-CEBPE translocated ALL. This suggests CEBPE regulates a similar set of genes in each, consistent with a common biological mechanism of leukemogenesis for rs2239630 associated and CEBPE translocated ALL. Finally, we map IGH-CEBPE translocation breakpoints in two cases, implicating RAG recombinase activity in their formation.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/genética , Cromossomos Humanos Par 14/genética , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Regiões Promotoras Genéticas , Biomarcadores Tumorais/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Estudos de Casos e Controles , Proliferação de Células , Epigenômica , Humanos , Análise em Microsséries , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Sequências Reguladoras de Ácido Nucleico , Translocação Genética , Células Tumorais Cultivadas
19.
Eur J Med Genet ; 62(1): 9-14, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29698806

RESUMO

DICER1 encodes an RNase III endonuclease protein that regulates the production of small non-coding RNAs. Germline mutations in DICER1 are associated with an autosomal dominant hereditary cancer predisposition syndrome that confers an increased risk for the development of several rare childhood and adult-onset tumors, the most frequent of which include pleuropulmonary blastoma, ovarian sex cord-stromal tumors, cystic nephroma, and thyroid gland neoplasia. The majority of reported germline DICER1 mutations are truncating sequence-level alterations, suggesting that a loss-of-function type mechanism drives tumor formation in DICER1 syndrome. However, reports of patients with germline DICER1 whole gene deletions are limited, and thus far, only two have reported an association with tumor development. Here we report the clinical findings of three patients from two unrelated families with 14q32 deletions that encompass the DICER1 locus. The deletion identified in Family I is 1.4 Mb and was initially identified in a 6-year-old male referred for developmental delay, hypotonia, macrocephaly, obesity, and behavioral problems. Subsequent testing revealed that this deletion was inherited from his mother, who had a clinical history that included bilateral multinodular goiter and papillary thyroid carcinoma. The second deletion is 5.0 Mb and was identified in a 15-year-old female who presented with autism, coarse facial features, Sertoli-Leydig cell tumor, and Wilms' tumor. These findings provide additional supportive evidence that germline deletion of DICER1 confers an increased risk for DICER1-related tumor development, and provide new insight into the clinical significance of deletions involving the 14q32 region.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 14/genética , RNA Helicases DEAD-box/genética , Deficiências do Desenvolvimento/genética , Neoplasias/genética , Ribonuclease III/genética , Adolescente , Adulto , Criança , Transtornos Cromossômicos/patologia , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Masculino , Neoplasias/patologia , Linhagem , Síndrome
20.
Genes Chromosomes Cancer ; 58(5): 284-294, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30411419

RESUMO

Common fragile sites (cFSs) represent parts of the normal chromosome structure susceptible to breakage under replication stress. Although only a small number of cFSs have been molecularly characterized, genomic damage of cFS genes appears to be critical for the development of various human diseases. In this study, we fine mapped the location of FRA14B and showed that the fragile region spans 765 kb at 14q23.3, containing the large gephyrin (GPHN) gene. The FRA14B sequence is enriched in perfect A/T>24 stretches and R-loop forming sequences (RLFS), and harbors a large palindromic motif in the core region. FRA14B instability is not only limited to lymphocytes, but also occurs in neuroblastoma and breast epithelial cells. Using array comparative genomic hybridization (CGH), we examined copy number alteration patterns within FRA14B in a panel of 180 cancer cell lines and primary tumors. Our CGH data and a survey of 1046 Cancer Cell Line Encyclopedia profiles demonstrate that focal deletions cluster within FRA14B and disrupt the genomic integrity of GPHN in approximately 5% of cancer cells. Moreover, germline CNVs (copy number variants) profiles provided by the Database of Genomic Variants and available literature suggest that germline CNVs and rare pathogenic deletions associated with neurodevelopmental disorders cluster within the core fragile region of GPHN. Overall, our data provide insight into the molecular structure of FRA14B, and identify GPHN, as a large cFS gene in the human genome, whose disruption appears to trigger various neurodevelopmental diseases.


Assuntos
Sítios Frágeis do Cromossomo , Cromossomos Humanos Par 14/genética , Deficiências do Desenvolvimento/genética , Neoplasias/genética , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Células Cultivadas , Variações do Número de Cópias de DNA , Mutação em Linhagem Germinativa , Humanos , Proteínas de Membrana/genética
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