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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(8): 777-780, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31400126

RESUMO

OBJECTIVE: To assess the value of detecting the rearrangement of mixed lineage leukemia (MLL) gene in children with acute mononuclear leukemia (AML). METHODS: Dual-color fluorescence in situ hybridization (FISH) probe was used to detect MLL gene rearrangement in 68 children with AML by interphase FISH. The results were compared with that of conventional G banding chromosomal analysis. RESULTS: Among the 68 children, 28 were detected by FISH with positive hybridization signals, with a detection rate for MLL gene rearrangement being 41.2%. Twelve (17.6%) reciprocal translocations and interruption of 11q23 were detected by G banding analysis. The difference in the detection rates between the two methods was statistically significant (P< 0.05). CONCLUSION: The sensitivity of FISH assay for MLL gene rearrangement was significantly higher than that of G banding chromosomal karyotyping. Combined use of both methods for children with AML can improve the detection rate of MLL gene rearrangements and provide crucial clues for clinical diagnosis, treatment and prognosis.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Leucemia Monocítica Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Criança , Cromossomos Humanos Par 11 , Rearranjo Gênico , Humanos , Hibridização in Situ Fluorescente , Translocação Genética
2.
Hum Genet ; 138(10): 1077-1090, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31172260

RESUMO

High hyperopia is a common and severe form of refractive error. Genetic factors play important roles in the development of high hyperopia but the exact gene responsible for this condition is mostly unknown. We identified a large Chinese family with autosomal dominant high hyperopia. A genome-wide linkage scan mapped the high hyperopia to chromosome 11p12-q13.3, with maximum log of the odds scores of 4.68 at theta = 0 for D11S987. Parallel whole-exome sequencing detected a novel c.3377delG (p.Gly1126Valfs*31) heterozygous mutation in the MYRF gene within the linkage interval. Whole-exome sequencing in other 121 probands with high hyperopia identified additional novel mutations in MYRF within two other families: a de novo c.3274_3275delAG (p.Leu1093Profs*22) heterozygous mutation and a c.3194+2T>C heterozygous mutation. All three mutations are located in the C-terminal region of MYRF and are predicted to result in truncation of that portion. Two patients from two of the three families developed angle-closure glaucoma. These three mutations were present in neither the ExAC database nor our in-house whole-exome sequencing data from 3280 individuals. No other truncation mutations in MYRF were detected in the 3280 individuals. Knockdown of myrf resulted in small eye size in zebrafish. These evidence all support that truncation mutations in the C-terminal region of MYRF are responsible for autosomal dominant high hyperopia in these families. Our results may provide useful clues for further understanding the functional role of the C-terminal region of this critical myelin regulatory factor, as well as the molecular pathogenesis of high hyperopia and its associated angle-closure glaucoma.


Assuntos
Cromossomos Humanos Par 11 , Oftalmopatias Hereditárias/genética , Genes Dominantes , Estudos de Associação Genética , Predisposição Genética para Doença , Hiperopia/genética , Proteínas de Membrana/genética , Mutação , Fatores de Transcrição/genética , Animais , Mapeamento Cromossômico , Análise Mutacional de DNA , Oftalmopatias Hereditárias/diagnóstico , Feminino , Angiofluoresceinografia , Técnicas de Inativação de Genes , Loci Gênicos , Humanos , Hiperopia/diagnóstico , Escore Lod , Masculino , Linhagem , Fenótipo , Peixe-Zebra
3.
Cytogenet Genome Res ; 157(4): 213-219, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30974445

RESUMO

Patients with childhood acute myeloid leukemia (AML) with complex karyotypes (CKs) have a dismal outcome. However, for patients with a KMT2A rearrangement (KMT2A-r), the prognosis appears to depend on the fusion partner gene rather than the karyotype structure. Thus, a precise characterization of KMT2A-r and the fusion partner genes, especially in CKs, is of interest for managing AML. We describe the clinical and molecular features of a child who presented with a large abdominal mass, AML, and a new CK, involving chromosomes 11, 16, and 19 leading to a KMT2A-MLLT1 fusion and 2 extra copies of the ELL gene, thus resulting in the concurrent overexpression of MLLT1 and ELL. Molecular cytogenetic studies defined the karyotype as 47,XY,der(11)t(11;16)(q23.3;p11.2),der(16)t(16;19)(p11.2;p13.3),der(19)t(11;19)(q23.3;p13.3),+der(19)t(16;19)(16pter→p11.2::19p13.3→19q11::19p11→19p13.3::16p11.2→16pter). Array CGH revealed a gain of 30.5 Mb in the 16p13.3p11.2 region and a gain of 18.1 Mb in the 19p13.3p12 region. LDI-PCR demonstrated the KMT2A-MLLT1 fusion. Reverse sequence analysis showed that the MLLT1 gene was fused to the 16p11.2 region. RT-qPCR quantification revealed that ELL and MLLT1 were overexpressed (4- and 10-fold, respectively). In summary, this is a pediatric case of AML presenting a novel complex t(11;16;19) variant with overexpression of ELL and MLLT1.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Fatores de Elongação da Transcrição/genética , Translocação Genética , Criança , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 19/genética , Humanos , Cariótipo , Masculino , Proteínas de Fusão Oncogênica/genética , Regulação para Cima
4.
Ann Hematol ; 98(7): 1675-1687, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30923996

RESUMO

Translocation (11;18)(q21;q21) is found in mucosa-associated lymphoid tissue (MALT) lymphoma, resulting in API2/MALT1 gene fusion. It is known that t(11;18)-positive MALT lymphoma shows a tendency to disseminate and be resistant to Helicobacter pylori eradication by antibiotics. However, the prognostic features including recurrence and histological transformation (HT) remain unknown. We conducted a single-institute retrospective analysis of 464 patients with newly diagnosed MALT lymphoma, evaluating the impact of t(11;18) on clinical outcomes. One hundred and six patients were screened for the translocation by fluorescence in situ hybridization and/or reverse transcriptase-polymerase chain reaction. Of these patients, 26 patients (25%) were diagnosed as MALT lymphoma with t(11;18). The patients had a significantly shortened progression-free survival (PFS at 10 years; 26% v 57%; P = 0.004) compared to those without t(11;18). However, this did not translate into overall survival or incidence of HT. We confirmed previous reports stating that t(11;18)-positive MALT lymphoma showed disseminated disease and refractoriness to H. pylori eradication therapy. Patients with t(11;18) had more frequent monoclonal gammopathy, especially of IgM subtype (31% v 8%; P = 0.008), some of which developed class switch. These findings characterize the features of t(11;18)-positive MALT lymphoma, suggesting that it comprises a distinct clinical entity of MALT lymphoma.


Assuntos
Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 18/genética , Linfoma de Zona Marginal Tipo Células B , Translocação Genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Hibridização in Situ Fluorescente , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida
5.
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
6.
Genet Res (Camb) ; 101: e3, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30829192

RESUMO

Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) are two imprinting disorders associated with opposite molecular alterations in the 11p15.5 imprinting centres. Their clinical diagnosis is confirmed by molecular testing in 50-70% of patients. The authors from different reference centres for BWS and SRS have identified single patients with unexpected and even contradictory molecular findings in respect to the clinical diagnosis. These patients clinically do not fit the characteristic phenotypes of SRS or BWS, but illustrate their clinical heterogeneity. Thus, comprehensive molecular testing is essential for accurate diagnosis and appropriate management, to avoid premature clinical diagnosis and anxiety for the families.


Assuntos
Síndrome de Beckwith-Wiedemann/genética , Síndrome de Silver-Russell/genética , Síndrome de Beckwith-Wiedemann/diagnóstico , Cromossomos Humanos Par 11/genética , Metilação de DNA , Predisposição Genética para Doença/genética , Testes Genéticos , Humanos , Fenótipo , Síndrome de Silver-Russell/diagnóstico
7.
BMC Med Genet ; 20(1): 27, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30704416

RESUMO

BACKGROUND: Myopia is one of most common eye diseases in the world and affects 1 in 4 Americans. It is a complex disease caused by both environmental and genetics effects; the genetics effects are still not well understood. In this study, we performed genetic linkage analyses on Ashkenazi Jewish families with a strong familial history of myopia to elucidate any potential causal genes. METHODS: Sixty-four extended Ashkenazi Jewish families were previously collected from New Jersey. Genotypes from the Illumina ExomePlus array were merged with prior microsatellite linkage data from these families. Additional custom markers were added for candidate regions reported in literature for myopia or refractive error. Myopia was defined as mean spherical equivalent (MSE) of -1D or worse and parametric two-point linkage analyses (using TwoPointLods) and multi-point linkage analyses (using SimWalk2) were performed as well as collapsed haplotype pattern (CHP) analysis in SEQLinkage and association analyses performed with FBAT and rv-TDT. RESULTS: Strongest evidence of linkage was on 1p36(two-point LOD = 4.47) a region previously linked to refractive error (MYP14) but not myopia. Another genome-wide significant locus was found on 8q24.22 with a maximum two-point LOD score of 3.75. CHP analysis also detected the signal on 1p36, localized to the LINC00339 gene with a maximum HLOD of 3.47, as well as genome-wide significant signals on 7q36.1 and 11p15, which overlaps with the MYP7 locus. CONCLUSIONS: We identified 2 novel linkage peaks for myopia on chromosomes 7 and 8 in these Ashkenazi Jewish families and replicated 2 more loci on chromosomes 1 and 11, one previously reported in refractive error but not myopia in these families and the other locus previously reported in the literature. Strong candidate genes have been identified within these linkage peaks in our families. Targeted sequencing in these regions will be necessary to definitively identify causal variants under these linkage peaks.


Assuntos
Cromossomos Humanos/genética , Técnicas de Genotipagem/métodos , Judeus/genética , Miopia/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 7/genética , Cromossomos Humanos Par 8/genética , Exoma , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Escore Lod , Masculino , Miopia/etnologia , Linhagem , RNA Longo não Codificante/genética
8.
Clin Epigenetics ; 11(1): 30, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30770769

RESUMO

BACKGROUND: Deletions of the imprinting centre 1 (IC1) in 11p15.5 are rare and their clinical significance is not only influenced by their parental origin but also by their exact genomic localization. In case the maternal IC1 allele is affected, the deletion is associated with the overgrowth disorder Beckwith-Wiedemann syndrome (BWS) and a gain of methylation (GOM) of the IC1. The consequences of deletions of the paternal IC1 allele depend on the localization and probably the binding sites of methylation-specific DNA-binding factors affected by the change. It has been suggested that distal deletions of the paternal allele are associated with a normal IC1 methylation and phenotype, whereas proximal alterations cause a loss of methylation (LOM) and Silver-Russell syndrome (SRS) features. RESULTS: In a patient referred for molecular BWS testing and his family, a deletion within the IC1 was identified by MLPA. It was associated with a GOM, corresponding to the transmission of the alteration via the maternal germline. Accordingly, the deletion was also detectable in the maternal grandmother, but here the paternal chromosome 11p15.5 was affected and a IC1 LOM was observed. By nanopore sequencing, the localization of the deletion could be precisely determined. CONCLUSIONS: We report for the first time both GOM and LOM of the IC1 in the same family, caused by transmission of a 2.2-kb deletion in 11p15.5. Nanopore sequencing allowed the precise characterization of the change by long-read sequencing and thereby provides further insights in the regulation of imprinting in the IC1.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 11/genética , Metilação de DNA , Análise de Sequência de DNA/métodos , Feminino , Impressão Genômica , Humanos , Masculino , Linhagem
10.
Int J Lab Hematol ; 41(2): 287-292, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30624859

RESUMO

INTRODUCTION: Translocations involving the KMT2A gene (also known as MLL) are frequently diagnosed in pediatric acute leukemia cases with either lymphoblastic or myeloid origin. KMT2A is translocated to multiple partner genes, including MLLT10/AF10 localizing at chromosomal band 10p12. KMT2A-MLLT10 is one of the common chimeric genes diagnosed in acute leukemia with KMT2A rearrangement (8%), especially in acute myeloid leukemia (AML; 18%). MLLT10 is localized in very close proximity to two other KMT2A partner genes at 10p11-12-NEBL and ABI1, so they could not be distinguished by conventional cytogenetics. METHODS: In this work, we present a cohort of 28 patients enrolled into Russian Pediatric AML registration study carrying rearrangements between chromosomal regions 11q23.3 and 10p11-12. G-banding, FISH, reverse transcription PCR, and long-distance inverse PCR were used to characterize the KMT2A gene rearrangements in these patients. RESULTS: We demonstrate that 25 patients harbor the KMT2A-MLLT10 rearrangement, while three patients show the rare KMT2A rearrangements (2× KMT2A-NEBL; 1× KMT2A-ABI1). CONCLUSIONS: Therefore, the combination of cytogenetic and molecular genetic methods is of high importance in diagnosing cases with t(10;11)(p11-12;q23.3).


Assuntos
Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 11/genética , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Sistema de Registros , Fatores de Transcrição/genética , Translocação Genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Leucemia Mieloide Aguda/patologia , Masculino
12.
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
13.
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
14.
J Pediatr Endocrinol Metab ; 32(2): 191-196, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30676999

RESUMO

Background Silver-Russell syndrome (SRS) is characterized by growth retardation and variable features including macrocephaly, body asymmetry, and genital manifestations such as cryptorchidism in 46,XY patients. Case presentation The patient was born at 39 weeks with a birth weight of 1344 g. Subtle clitoromegaly warranted a thorough evaluation, which disclosed 46,XY karyotype, bilateral undescended testes, and a rudimentary uterus. Because of severe under-virilization, the patient was assigned as female. Failure to thrive, macrocephaly, and body asymmetry led to the diagnosis of SRS, confirmed by marked hypomethylation of H19/IGF2 intergenic differentially methylated region (IG-DMR). From age 9 years, progressive virilization occurred, which necessitated luteinizing hormone-releasing hormone analog (LHRHa) treatment. Gonadal resection at 15 years revealed immature testes with mostly Sertoli-cell-only tubules. Panel analysis for 46,XY-differences of sex development (DSD) failed to detect any pathogenic variants. Conclusions This is the second reported case of molecularly proven 46,XY SRS accompanied by severe under-virilization. SRS should be included in the differential diagnosis of 46,XY-DSD.


Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 11 , Metilação de DNA , Genitália/anormalidades , Síndrome de Silver-Russell/patologia , Virilismo , Anormalidades Múltiplas/classificação , Feminino , Genitália/crescimento & desenvolvimento , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Fenótipo , Gravidez , Prognóstico , Índice de Gravidade de Doença , Síndrome de Silver-Russell/genética
16.
Blood ; 133(9): 962-966, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30567752

RESUMO

The new recently described provisional lymphoma category Burkitt-like lymphoma with 11q aberration comprises cases similar to Burkitt lymphoma (BL) on morphological, immunophenotypic and gene-expression levels but lacking the IG-MYC translocation. They are characterized by a peculiar imbalance pattern on chromosome 11, but the landscape of mutations is not yet described. Thus, we investigated 15 MYC-negative Burkitt-like lymphoma with 11q aberration (mnBLL,11q,) cases by copy-number analysis and whole-exome sequencing. We refined the regions of 11q imbalance and identified the INO80 complex-associated gene NFRKB as a positional candidate in 11q24.3. Next to recurrent gains in 12q13.11-q24.32 and 7q34-qter as well as losses in 13q32.3-q34, we identified 47 genes recurrently affected by protein-changing mutations (each ≥3 of 15 cases). Strikingly, we did not detect recurrent mutations in genes of the ID3-TCF3 axis or the SWI/SNF complex that are frequently altered in BL, or in genes frequently mutated in germinal center-derived B-cell lymphomas like KMT2D or CREBBP An exception is GNA13, which was mutated in 7 of 15 cases. We conclude that the genomic landscape of mnBLL,11q, differs from that of BL both at the chromosomal and mutational levels. Our findings implicate that mnBLL,11q, is a lymphoma category distinct from BL at the molecular level.


Assuntos
Biomarcadores Tumorais/genética , Linfoma de Burkitt/classificação , Linfoma de Burkitt/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 11/genética , Mutação , Adolescente , Adulto , Linfoma de Burkitt/patologia , Criança , Pré-Escolar , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-myc/genética , Estudos Retrospectivos , Adulto Jovem
17.
Cancer Genet ; 228-229: 110-114, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30553463

RESUMO

We present a case of an infant who developed pro-B acute lymphoblastic leukemia with a rare and complex MLL-translocation. Cytogenetic analysis of bone marrow cells at diagnosis showed a 46,XY,t(X;11)(p11.2;q23)[13]/46,XY[7] karyotype. Fluorescence in situ hybridization analysis using a break apart specific probes showed a split in the MLL gene. Long distance inverse-PCR and next generation sequencing analysis depicted a complex rearrangement t(X;11;17)(p11.2;q23;q12) involving MLL, MLLT6 and the genomic region Xp11.23, 41 bases upstream of the WDR45 gene. WDR45 encodes a beta-propeller protein essential for autophagocytosis. MLL rearrangements with involvement of Xp have not been previously described.


Assuntos
Cromossomos Humanos Par 11 , Cromossomos Humanos Par 17 , Cromossomos Humanos X , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética , Proteínas de Transporte/genética , Proteínas de Ligação a DNA/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Lactente , Masculino , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Neoplasias/genética
18.
Cytogenet Genome Res ; 156(4): 185-190, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30566958

RESUMO

The AT-rich repeat on chromosome 22q11.2 is known to be involved in the recurrent constitutional t(11;22)(q23;q11.2). Segregation of this translocation has been reported in several hundred families, but a de novo translocation event has been identified in only 8 cases, and everytime the translocation originated in paternal germ-line chromosomes. Further, de novo t(11;22) rearrangements have been detected in the sperm of healthy males, leading to the hypothesis that it occurs somewhere along the meiosis-spermatogenesis pathway. This report describes a woman whose constitutional karyotype revealed mosaicism for the recurrent t(11;22) and the subsequent testing performed to determine the origin of the translocation event. Karyotype analysis, translocation-specific PCR, human identity testing, and a SNP genotyping array were performed to detect mosaicism and/or chimerism. As a result, the SNP genotyping array revealed no evidence for mosaicism in genomic DNA beyond mosaicism for the balanced t(11;22). Human identity testing and the SNP genotyping array ruled out chimerism. PCR of the translocation breakpoint followed by sequencing confirmed that the translocation had occurred at the typical t(11;22) breakpoints. In conclusion, these results indicate that the translocation occurred post-fertilization, providing the first evidence of a de novo t(11;22)(q23;q11.2) occurring in a maternal mitotic environment.


Assuntos
Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 22/genética , Translocação Genética , Aborto Espontâneo/genética , Adulto , Feminino , Humanos , Cariótipo , Mosaicismo , Síndrome do Ovário Policístico/genética , Análise de Sequência de DNA
19.
PLoS One ; 13(12): e0206579, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30540749

RESUMO

Multistage tumorigenesis is a dynamic process characterized by the accumulation of mutations. Thus, a tumor mass is composed of genetically divergent cell subclones. With the advancement of next-generation sequencing (NGS), mathematical models have been recently developed to decompose tumor subclonal architecture from a collective genome sequencing data. Most of the methods focused on single-nucleotide variants (SNVs). However, somatic copy number aberrations (CNAs) also play critical roles in carcinogenesis. Therefore, further modeling subclonal CNAs composition would hold the promise to improve the analysis of tumor heterogeneity and cancer evolution. To address this issue, we developed a two-way mixture Poisson model, named CloneDeMix for the deconvolution of read-depth information. It can infer the subclonal copy number, mutational cellular prevalence (MCP), subclone composition, and the order in which mutations occurred in the evolutionary hierarchy. The performance of CloneDeMix was systematically assessed in simulations. As a result, the accuracy of CNA inference was nearly 93% and the MCP was also accurately restored. Furthermore, we also demonstrated its applicability using head and neck cancer samples from TCGA. Our results inform about the extent of subclonal CNA diversity, and a group of candidate genes that probably initiate lymph node metastasis during tumor evolution was also discovered. Most importantly, these driver genes are located at 11q13.3 which is highly susceptible to copy number change in head and neck cancer genomes. This study successfully estimates subclonal CNAs and exhibit the evolutionary relationships of mutation events. By doing so, we can track tumor heterogeneity and identify crucial mutations during evolution process. Hence, it facilitates not only understanding the cancer development but finding potential therapeutic targets. Briefly, this framework has implications for improved modeling of tumor evolution and the importance of inclusion of subclonal CNAs.


Assuntos
Cromossomos Humanos Par 11/genética , Simulação por Computador , Variações do Número de Cópias de DNA , Neoplasias de Cabeça e Pescoço/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Humanos
20.
Genes Chromosomes Cancer ; 57(10): 522-524, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30107050

RESUMO

We present a leukemia case that exhibits a chromosomal translocation t(11;16)(q23;q23), which results in the expression of a novel KMT2A fusion gene. This novel fusion, KMT2A-USP10, was found in a relapse of acute myeloid leukaemia M5a. USP10 belongs to a protein family that deubiquitinates a distinct set of target proteins, and thus, increases the steady state protein levels of its target subproteome. One of the USP10 targets is TP53. Wildtype TP53 is usually rescued from proteasomal degradation by USP10. As most KMT2A leukemias display wildtype p53 alleles, one might argue that the disruption of an USP10 allele can be classified as a pro-oncogenic event.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Translocação Genética/genética , Ubiquitina Tiolesterase/genética , Adolescente , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 16/genética , Humanos , Cariotipagem , Leucemia Mieloide Aguda/patologia , Masculino , Proteínas de Fusão Oncogênica/genética , Proteína Supressora de Tumor p53/genética
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