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1.
Nature ; 553(7689): 511-514, 2018 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-29342136

RESUMO

Relapsed acute lymphoblastic leukaemia (ALL) is associated with resistance to chemotherapy and poor prognosis. Gain-of-function mutations in the 5'-nucleotidase, cytosolic II (NT5C2) gene induce resistance to 6-mercaptopurine and are selectively present in relapsed ALL. Yet, the mechanisms involved in NT5C2 mutation-driven clonal evolution during the initiation of leukaemia, disease progression and relapse remain unknown. Here we use a conditional-and-inducible leukaemia model to demonstrate that expression of NT5C2(R367Q), a highly prevalent relapsed-ALL NT5C2 mutation, induces resistance to chemotherapy with 6-mercaptopurine at the cost of impaired leukaemia cell growth and leukaemia-initiating cell activity. The loss-of-fitness phenotype of NT5C2+/R367Q mutant cells is associated with excess export of purines to the extracellular space and depletion of the intracellular purine-nucleotide pool. Consequently, blocking guanosine synthesis by inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH) induced increased cytotoxicity against NT5C2-mutant leukaemia lymphoblasts. These results identify the fitness cost of NT5C2 mutation and resistance to chemotherapy as key evolutionary drivers that shape clonal evolution in relapsed ALL and support a role for IMPDH inhibition in the treatment of ALL.


Assuntos
5'-Nucleotidase/genética , 5'-Nucleotidase/metabolismo , Evolução Clonal , Resistencia a Medicamentos Antineoplásicos/genética , Mutação/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Animais , Proliferação de Células , Modelos Animais de Doenças , Feminino , Mutação com Ganho de Função/genética , Guanosina/biossíntese , Células HEK293 , Humanos , IMP Desidrogenase/antagonistas & inibidores , IMP Desidrogenase/metabolismo , Masculino , Mercaptopurina/farmacologia , Mercaptopurina/uso terapêutico , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Purinas/metabolismo , Receptor Notch1/metabolismo , Recidiva , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Br J Haematol ; 200(2): 249-255, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36177683

RESUMO

Erythrocytosis is associated with increased red blood cell mass and can be either congenital or acquired. Congenital secondary causes are rare and include germline variants increasing haemoglobin (Hb)-oxygen affinity (e.g., Hb or bisphosphoglycerate mutase (BPGM) variants) or affecting oxygen-sensing pathway proteins. Here, we describe five adults from three kindreds with erythrocytosis associated with heterozygosity for BPGM variants, including one novel. Functional analyses showed partial BPGM deficiency, reduced 2,3-bisphosphoglycerate levels and/or increased Hb-oxygen affinity. We also review currently known BPGM variants. This study contributes to raising awareness of BPGM variants, and in particular that heterozygosity for BPGM deficiency may already manifest clinically.


Assuntos
Anemia Hemolítica , Erros Inatos do Metabolismo , Policitemia , Adulto , Humanos , Bisfosfoglicerato Mutase/genética , Policitemia/congênito , Heterozigoto , Hemoglobinas , Oxigênio
3.
Am J Hum Genet ; 104(4): 758-766, 2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30929739

RESUMO

By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature. The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella. Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood. KDM3B encodes for a histone demethylase and is involved in H3K9 demethylation, a crucial part of chromatin modification required for transcriptional regulation. We identified missense and truncating variants, suggesting that KDM3B haploinsufficiency is the underlying mechanism for this syndrome. By using a hybrid facial-recognition model, we show that individuals with a pathogenic variant in KDM3B have a facial gestalt, and that they show significant facial similarity compared to control individuals with ID. In conclusion, pathogenic variants in KDM3B cause a syndrome characterized by ID, short stature, and facial dysmorphism.


Assuntos
Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Nanismo/genética , Variação Genética , Deficiência Intelectual/genética , Histona Desmetilases com o Domínio Jumonji/genética , Anormalidades Musculoesqueléticas/genética , Estatura , Criança , Exoma , Face , Feminino , Estudos de Associação Genética , Mutação em Linhagem Germinativa , Haploinsuficiência , Histonas/química , Humanos , Masculino , Mutação de Sentido Incorreto , Fenótipo
4.
Pediatr Blood Cancer ; 69(6): e29582, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35316565

RESUMO

BACKGROUND: White blood cell count (WBC) as a measure of extramedullary leukemic cell survival is a well-known prognostic factor in acute lymphoblastic leukemia (ALL), but its biology, including impact of host genome variants, is poorly understood. METHODS: We included patients treated with the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-2008 protocol (N = 2347, 72% were genotyped by Illumina Omni2.5exome-8-Bead chip) aged 1-45 years, diagnosed with B-cell precursor (BCP-) or T-cell ALL (T-ALL) to investigate the variation in WBC. Spline functions of WBC were fitted correcting for association with age across ALL subgroups of immunophenotypes and karyotypes. The residuals between spline WBC and actual WBC were used to identify WBC-associated germline genetic variants in a genome-wide association study (GWAS) while adjusting for age and ALL subtype associations. RESULTS: We observed an overall inverse correlation between age and WBC, which was stronger for the selected patient subgroups of immunophenotype and karyotypes (ρBCP-ALL  = -.17, ρT-ALL  = -.19; p < 3 × 10-4 ). Spline functions fitted to age, immunophenotype, and karyotype explained WBC variation better than age alone (ρ = .43, p << 2 × 10-6 ). However, when the spline-adjusted WBC residuals were used as phenotype, no GWAS significant associations were found. Based on available annotation, the top 50 genetic variants suggested effects on signal transduction, translation initiation, cell development, and proliferation. CONCLUSION: These results indicate that host genome variants do not strongly influence WBC across ALL subsets, and future studies of why some patients are more prone to hyperleukocytosis should be performed within specific ALL subsets that apply more complex analyses to capture potential germline variant interactions and impact on WBC.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Contagem de Leucócitos , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico
5.
Pediatr Blood Cancer ; 69(1): e29361, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34597466

RESUMO

INTRODUCTION: One-quarter of the relapses in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) occur very early (within 18 months, before completion of treatment), and prognosis in these patients is worse compared to cases that relapse after treatment has ended. METHODS: In this study, we performed a genomic analysis of diagnosis-relapse pairs of 12 children who relapsed very early, followed by a deep-sequencing validation of all identified mutations. In addition, we included one case with a good initial treatment response and on-treatment relapse at the end of upfront therapy. RESULTS: We observed a dynamic clonal evolution in all cases, with relapse almost exclusively originating from a subclone at diagnosis. We identified several driver mutations that may have influenced the outgrowth of a minor clone at diagnosis to become the major clone at relapse. For example, a minimal residual disease (MRD)-based standard-risk patient with ETV6-RUNX1-positive leukemia developed a relapse from a TP53-mutated subclone after loss of the wildtype allele. Furthermore, two patients with TCF3-PBX1-positive leukemia that developed a very early relapse carried E1099K WHSC1 mutations at diagnosis, a hotspot mutation that was recurrently encountered in other very early TCF3-PBX1-positive leukemia relapses as well. In addition to alterations in known relapse drivers, we found two cases with truncating mutations in the cohesin gene RAD21. CONCLUSION: Comprehensive genomic characterization of diagnosis-relapse pairs shows that very early relapses in BCP-ALL frequently arise from minor subclones at diagnosis. A detailed understanding of the therapeutic pressure driving these events may aid the development of improved therapies.


Assuntos
Doença Enxerto-Hospedeiro , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Evolução Clonal/genética , Genômica , Humanos , Prognóstico , Recidiva
6.
J Pathol ; 255(2): 202-211, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34231212

RESUMO

In a subset of pediatric cancers, a germline cancer predisposition is highly suspected based on clinical and pathological findings, but genetic evidence is lacking, which hampers genetic counseling and predictive testing in the families involved. We describe a family with two siblings born from healthy parents who were both neonatally diagnosed with atypical teratoid rhabdoid tumor (ATRT). This rare and aggressive pediatric tumor is associated with biallelic inactivation of SMARCB1, and in 30% of the cases, a predisposing germline mutation is involved. Whereas the tumors of both siblings showed loss of expression of SMARCB1 and acquired homozygosity of the locus, whole exome and whole genome sequencing failed to identify germline or somatic SMARCB1 pathogenic mutations. We therefore hypothesized that the insertion of a pathogenic repeat-rich structure might hamper its detection, and we performed optical genome mapping (OGM) as an alternative strategy to identify structural variation in this locus. Using this approach, an insertion of ~2.8 kb within intron 2 of SMARCB1 was detected. Long-range PCR covering this region remained unsuccessful, but PacBio HiFi genome sequencing identified this insertion to be a SINE-VNTR-Alu, subfamily E (SVA-E) retrotransposon element, which was present in a mosaic state in the mother. This SVA-E insertion disrupts correct splicing of the gene, resulting in loss of a functional allele. This case demonstrates the power of OGM and long-read sequencing to identify genomic variations in high-risk cancer-predisposing genes that are refractory to detection with standard techniques, thereby completing the clinical and molecular diagnosis of such complex cases and greatly improving counseling and surveillance of the families involved. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.


Assuntos
Mapeamento Cromossômico/métodos , Retroelementos/genética , Tumor Rabdoide/genética , Proteína SMARCB1/genética , Teratoma/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Recém-Nascido , Tumor Rabdoide/congênito , Irmãos , Teratoma/congênito
7.
Haematologica ; 106(12): 3046-3055, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33147938

RESUMO

Genomic studies of pediatric acute lymphoblastic leukemia (ALL) have shown remarkable heterogeneity in initial diagnosis, with multiple (sub)clones harboring lesions in relapse-associated genes. However, the clinical relevance of these subclonal alterations remains unclear. We assessed the clinical relevance and prognostic value of subclonal alterations in the relapse-associated genes IKZF1, CREBBP, KRAS, NRAS, PTPN11, TP53, NT5C2, and WHSC1 in 503 ALL cases. Using Molecular Inversion Probe sequencing and breakpoint-spanning PCR we reliably detected alterations below 1% allele frequency. We identified 660 genomic alterations in 285 diagnosis samples of which 495 (75%) were subclonal. RAS pathway mutations were common, particularly in minor subclones, and comparisons between RAS hotspot mutations revealed differences in their capacity to drive clonal expansion in ALL. We did not find an association of subclonal alterations with unfavorable outcome. Particularly for IKZF1, an established prognostic marker in ALL, all clonal but none of the subclonal alterations were preserved at relapse. We conclude that, for the genes tested, there is no basis to consider subclonal alterations detected at diagnosis for risk group stratification of ALL treatment.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Células Clonais , Genômica , Humanos , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico
8.
Int J Cancer ; 145(4): 941-951, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30694527

RESUMO

Two percent of patients with Wilms tumors have a positive family history. In many of these cases the genetic cause remains unresolved. By applying germline exome sequencing in two families with two affected individuals with Wilms tumors, we identified truncating mutations in TRIM28. Subsequent mutational screening of germline and tumor DNA of 269 children affected by Wilms tumor was performed, and revealed seven additional individuals with germline truncating mutations, and one individual with a somatic truncating mutation in TRIM28. TRIM28 encodes a complex scaffold protein involved in many different processes, including gene silencing, DNA repair and maintenance of genomic integrity. Expression studies on mRNA and protein level showed reduction of TRIM28, confirming a loss-of-function effect of the mutations identified. The tumors showed an epithelial-type histology that stained negative for TRIM28 by immunohistochemistry. The tumors were bilateral in six patients, and 10/11 tumors are accompanied by perilobar nephrogenic rests. Exome sequencing on eight tumor DNA samples from six individuals showed loss-of-heterozygosity (LOH) of the TRIM28-locus by mitotic recombination in seven tumors, suggesting that TRIM28 functions as a tumor suppressor gene in Wilms tumor development. Additionally, the tumors showed very few mutations in known Wilms tumor driver genes, suggesting that loss of TRIM28 is the main driver of tumorigenesis. In conclusion, we identified heterozygous germline truncating mutations in TRIM28 in 11 children with mainly epithelial-type Wilms tumors, which become homozygous in tumor tissue. These data establish TRIM28 as a novel Wilms tumor predisposition gene, acting as a tumor suppressor gene by LOH.


Assuntos
Haploinsuficiência/genética , Proteína 28 com Motivo Tripartido/genética , Tumor de Wilms/genética , Carcinogênese/genética , Pré-Escolar , DNA de Neoplasias/genética , Feminino , Genes do Tumor de Wilms/fisiologia , Predisposição Genética para Doença/genética , Genótipo , Mutação em Linhagem Germinativa/genética , Heterozigoto , Humanos , Lactente , Neoplasias Renais/genética , Mutação com Perda de Função/genética , Perda de Heterozigosidade/genética , Masculino , Sequenciamento do Exoma/métodos
9.
Haematologica ; 102(3): 541-551, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27979924

RESUMO

Deletions and mutations affecting lymphoid transcription factor IKZF1 (IKAROS) are associated with an increased relapse risk and poor outcome in B-cell precursor acute lymphoblastic leukemia. However, additional genetic events may either enhance or negate the effects of IKZF1 deletions on prognosis. In a large discovery cohort of 533 childhood B-cell precursor acute lymphoblastic leukemia patients, we observed that single-copy losses of BTG1 were significantly enriched in IKZF1-deleted B-cell precursor acute lymphoblastic leukemia (P=0.007). While BTG1 deletions alone had no impact on prognosis, the combined presence of BTG1 and IKZF1 deletions was associated with a significantly lower 5-year event-free survival (P=0.0003) and a higher 5-year cumulative incidence of relapse (P=0.005), when compared with IKZF1-deleted cases without BTG1 aberrations. In contrast, other copy number losses commonly observed in B-cell precursor acute lymphoblastic leukemia, such as CDKN2A/B, PAX5, EBF1 or RB1, did not affect the outcome of IKZF1-deleted acute lymphoblastic leukemia patients. To establish whether the combined loss of IKZF1 and BTG1 function cooperate in leukemogenesis, Btg1-deficient mice were crossed onto an Ikzf1 heterozygous background. We observed that loss of Btg1 increased the tumor incidence of Ikzf1+/- mice in a dose-dependent manner. Moreover, murine B cells deficient for Btg1 and Ikzf1+/- displayed increased resistance to glucocorticoids, but not to other chemotherapeutic drugs. Together, our results identify BTG1 as a tumor suppressor in leukemia that, when deleted, strongly enhances the risk of relapse in IKZF1-deleted B-cell precursor acute lymphoblastic leukemia, and augments the glucocorticoid resistance phenotype mediated by the loss of IKZF1 function.


Assuntos
Transformação Celular Neoplásica/genética , Epistasia Genética , Fator de Transcrição Ikaros/genética , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Animais , Biomarcadores Tumorais , Transformação Celular Neoplásica/metabolismo , Criança , Pré-Escolar , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Deleção de Genes , Predisposição Genética para Doença , Humanos , Fator de Transcrição Ikaros/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/metabolismo , Avaliação de Resultados da Assistência ao Paciente , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Prognóstico , Recidiva , Proteínas Supressoras de Tumor/metabolismo
10.
J Clin Lab Anal ; 30(5): 431-6, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26365003

RESUMO

BACKGROUND: Isolated polycystic liver disease (ADPLD) is an autosomal dominant Mendelian disorder. Heterozygous PRKCSH (where PRKCSH is protein kinase C substrate 80K-H (80 kDa protein, heavy chain; MIM*177060) mutations are the most frequent cause. Routine molecular testing using Sanger sequencing identifies pathogenic variants in the PRKCSH (15%) and SEC63 (where SEC63 is Saccharomyces cerevisiae homolog 63 (MIM*608648); 6%) genes, but about approximately 80% of patients meeting the clinical ADPLD criteria carry no PRKCSH or SEC63 mutation. Cyst tissue often shows somatic deletions with loss of heterozygosity that was recently recognized as a general mechanism in ADPLD. We hypothesized that germline deletions in the PRKCSH gene may be responsible for hepatic cystogenesis in a significant number of mutation-negative ADPLD patients. METHODS: In this study, we designed a multiplex ligation-dependent probe amplification (MLPA) assay to screen for deletions of PRKCSH exons. Genomic DNA from 60 patients with an ADPLD phenotype was included. RESULTS: MLPA analysis detected no exon deletions in mutation-negative ADPLD patients. CONCLUSION: Large copy number variations on germline level are not present in patients with a clinical diagnosis of ADPLD. MLPA analysis of the PRKCSH gene should not be considered as a diagnostic method to explain hepatic cystogenesis.


Assuntos
Cistos/genética , Glucosidases/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Hepatopatias/genética , Deleção de Sequência/genética , Adulto , Idoso , Proteínas de Ligação ao Cálcio , Feminino , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Chaperonas Moleculares , Reação em Cadeia da Polimerase Multiplex/métodos , Proteínas de Ligação a RNA , Estudos Retrospectivos
11.
Blood ; 122(15): 2622-9, 2013 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-23974192

RESUMO

Most relapses in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are not predicted using current prognostic features. Here, we determined the co-occurrence and independent prognostic relevance of 3 recently identified prognostic features: BCR-ABL1-like gene signature, deletions in IKZF1, and high CRLF2 messenger RNA expression (CRLF2-high). These features were determined in 4 trials representing 1128 children with ALL: DCOG ALL-8, ALL9, ALL10, and Cooperative ALL (COALL)-97/03. BCR-ABL1-like, IKZF1-deleted, and CRLF2-high cases constitute 33.7% of BCR-ABL1-negative, MLL wild-type BCP-ALL cases, of which BCR-ABL1-like and IKZF1 deletion (co)occurred most frequently. Higher cumulative incidence of relapse was found for BCR-ABL1-like and IKZF1-deleted, but not CRLF2-high, cases relative to remaining BCP-ALL cases, reflecting the observations in each of the cohorts analyzed separately. No relapses occurred among cases with CRLF2-high as single feature, whereas 62.9% of all relapses in BCR-ABL1-negative, MLL wild-type BCP-ALL occurred in cases with BCR-ABL1-like signature and/or IKZF1 deletion. Both the BCR-ABL1-like signature and IKZF1 deletions were prognostic features independent of conventional prognostic markers in a multivariate model, and both remained prognostic among cases with intermediate minimal residual disease. The BCR-ABL1-like signature and an IKZF1 deletion, but not CRLF2-high, are prognostic factors and are clinically of importance to identify high-risk patients who require more intensive and/or alternative therapies.


Assuntos
Proteínas de Fusão bcr-abl/genética , Fator de Transcrição Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptores de Citocinas/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Valor Preditivo dos Testes , Prognóstico , Recidiva , Fatores de Risco
12.
PLoS Genet ; 8(2): e1002533, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22359517

RESUMO

Recurrent submicroscopic deletions in genes affecting key cellular pathways are a hallmark of pediatric acute lymphoblastic leukemia (ALL). To gain more insight into the mechanism underlying these deletions, we have studied the occurrence and nature of abnormalities in one of these genes, the B-cell translocation gene 1 (BTG1), in a large cohort of pediatric ALL cases. BTG1 was found to be exclusively affected by genomic deletions, which were detected in 65 out of 722 B-cell precursor ALL (BCP-ALL) patient samples (9%), but not in 109 T-ALL cases. Eight different deletion sizes were identified, which all clustered at the telomeric site in a hotspot region within the second (and last) exon of the BTG1 gene, resulting in the expression of truncated BTG1 read-through transcripts. The presence of V(D)J recombination signal sequences at both sites of virtually all deletions strongly suggests illegitimate RAG1/RAG2-mediated recombination as the responsible mechanism. Moreover, high levels of histone H3 lysine 4 trimethylation (H3K4me3), which is known to tether the RAG enzyme complex to DNA, were found within the BTG1 gene body in BCP-ALL cells, but not T-ALL cells. BTG1 deletions were rarely found in hyperdiploid BCP-ALLs, but were predominant in other cytogenetic subgroups, including the ETV6-RUNX1 and BCR-ABL1 positive BCP-ALL subgroups. Through sensitive PCR-based screening, we identified multiple additional BTG1 deletions at the subclonal level in BCP-ALL, with equal cytogenetic distribution which, in some cases, grew out into the major clone at relapse. Taken together, our results indicate that BTG1 deletions may act as "drivers" of leukemogenesis in specific BCP-ALL subgroups, in which they can arise independently in multiple subclones at sites that are prone to aberrant RAG1/RAG2-mediated recombination events. These findings provide further evidence for a complex and multiclonal evolution of ALL.


Assuntos
Evolução Clonal , Deleção de Genes , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Doença Aguda , Criança , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Células Precursoras de Linfócitos B/metabolismo , Células Precursoras de Linfócitos B/patologia
13.
Eur J Med Genet ; 66(4): 104727, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36775010

RESUMO

Although hematologic malignancies (HM) are no longer considered exclusively sporadic, additional awareness of familial cases has yet to be created. Individuals carrying a (likely) pathogenic germline variant (e.g., in ETV6, GATA2, SAMD9, SAMD9L, or RUNX1) are at an increased risk for developing HM. Given the clinical and psychological impact associated with the diagnosis of a genetic predisposition to HM, it is of utmost importance to provide high-quality, standardized patient care. To address these issues and harmonize care across Europe, the Familial Leukemia Subnetwork within the ERN PaedCan has been assigned to draft an European Standard Clinical Practice (ESCP) document reflecting current best practices for pediatric patients and (healthy) relatives with (suspected) familial leukemia. The group was supported by members of the German network for rare diseases MyPred, of the Host Genome Working Group of SIOPE, and of the COST action LEGEND. The ESCP on familial leukemia is proposed by an interdisciplinary team of experts including hematologists, oncologists, and human geneticists. It is intended to provide general recommendations in areas where disease-specific recommendations do not yet exist. Here, we describe key issues for the medical care of familial leukemia that shall pave the way for a future consensus guideline: (i) identification of individuals with or suggestive of familial leukemia, (ii) genetic analysis and variant interpretation, (iii) genetic counseling and patient education, and (iv) surveillance and (psychological) support. To address the question on how to proceed with individuals suggestive of or at risk of familial leukemia, we developed an algorithm covering four different, partially linked clinical scenarios, and additionally a decision tree to guide clinicians in their considerations regarding familial leukemia in minors with HM. Our recommendations cover, not only patients but also relatives that both should have access to adequate medical care. We illustrate the importance of natural history studies and the need for respective registries for future evidence-based recommendations that shall be updated as new evidence-based standards are established.


Assuntos
Predisposição Genética para Doença , Leucemia , Humanos , Criança , Aconselhamento Genético , Mutação em Linhagem Germinativa , Fatores de Transcrição , Peptídeos e Proteínas de Sinalização Intracelular
14.
Gastroenterology ; 141(6): 2056-2063.e2, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21856269

RESUMO

BACKGROUND & AIMS: Heterozygous germline mutations in PRKCSH cause autosomal dominant polycystic liver disease (PCLD), but it is not clear how they lead to cyst formation. We investigated whether mutations in cyst epithelial cells and corresponding loss of the PRKCSH gene product (hepatocystin) contributed to cyst development. METHODS: Liver cyst material was collected through laparoscopic cyst fenestration from 8 patients with PCLD who had a heterozygous germline mutation in PRKCSH. Tissue sections from 71 cysts (2-14 per patient) were obtained for hepatocystin staining and mutation analysis. Cyst epithelium was acquired using laser microdissection; DNA was isolated and analyzed for loss of heterozygosity (LOH) and somatic mutations using restriction analysis and sequencing. Common single nucleotide polymorphisms (SNPs) in a 70-kilobase region surrounding the germline mutation were used to determine variations in the genomic region with LOH. RESULTS: The wild-type allele of PRKCSH was lost (LOH) in 76% of cysts (54/71). Hepatocystin was not detected in cyst epithelia with LOH, whereas heterozygous cysts still expressed hepatocystin. The variation observed in the LOH region analysis indicates that cysts develop independently. We also detected somatic mutations in PRKCSH in 17% (2/12) of the cysts without LOH. Trans-heterozygous mutations in SEC63 were not observed. CONCLUSIONS: Among patients with PCLD who have a heterozygous germline mutation in PRKCSH, we found secondary, somatic mutations (second hits) in more than 76% of the liver cyst epithelia. PCLD is recessive at the cellular level, and loss of functional PRKCSH is an important step in cystogenesis.


Assuntos
Cistos/genética , Glucosidases/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Hepatopatias/genética , Perda de Heterozigosidade , Mutação/genética , Adulto , Proteínas de Ligação ao Cálcio , Cistos/fisiopatologia , Análise Mutacional de DNA , Feminino , Mutação em Linhagem Germinativa , Humanos , Hepatopatias/fisiopatologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
15.
Blood ; 115(23): 4810-9, 2010 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-20354172

RESUMO

Resistance to glucocorticoids (GCs) is a major clinical problem in the treatment of acute lymphoblastic leukemia (ALL), but the underlying mechanisms are not well understood. Although mutations in the glucocorticoid receptor (GR) gene can give rise to therapy resistance in vitro, acquired somatic mutations in the GR are rarely encountered in patients. Here we report that the protein encoded by the BTG1 gene, which is frequently deleted in (pediatric) ALL, is a key determinant of GC responsiveness. Using RNA interference, we show that loss of BTG1 expression causes GC resistance both by decimating GR expression and by controlling GR-mediated transcription. Conversely, reexpression of BTG1 restores GC sensitivity by potentiating GC-induced GR expression, a phenomenon known as GR autoinduction. In addition, the arginine methyltransferase PRMT1, a BTG1-binding partner and transcriptional coactivator, is recruited to the GR gene promoter in a BTG1-dependent manner. These results implicate the BTG1/PRMT1 complex in GR-mediated gene expression and reveal that deregulation of a nuclear receptor coactivator complex can give rise to GC resistance. Further characterization of this complex as part of the GR regulatory circuitry could offer novel opportunities for improving the efficacy of GC-based therapies in ALL and other hematologic malignancies.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Regulação Leucêmica da Expressão Gênica , Proteínas de Neoplasias/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Receptores de Glucocorticoides/biossíntese , Linhagem Celular Tumoral , Feminino , Deleção de Genes , Glucocorticoides/efeitos adversos , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Masculino , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Regiões Promotoras Genéticas/genética , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Interferência de RNA , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/genética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/genética
17.
Genes Chromosomes Cancer ; 50(12): 969-81, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21882283

RESUMO

In acute lymphoblastic leukemia (ALL) specific genomic abnormalities provide important clinical information. In most routine clinical diagnostic laboratories conventional karyotyping, in conjunction with targeted screens using e.g., fluorescence in situ hybridization (FISH), is currently considered as the gold standard to detect such aberrations. Conventional karyotyping, however, is limited in its resolution and yield, thus hampering the genetic diagnosis of ALL. We explored whether microarray-based genomic profiling would be feasible as an alternative strategy in a routine clinical diagnostic setting. To this end, we compared conventional karyotypes with microarray-deduced copy number aberration (CNA) karyotypes in 60 ALL cases. Microarray-based genomic profiling resulted in a CNA detection rate of 90%, whereas for conventional karyotyping this was 61%. In addition, many small (< 5 Mb) genetic lesions were encountered, frequently harboring clinically relevant ALL-related genes such as CDKN2A/B, ETV6, PAX5, and IKZF1. From our data we conclude that microarray-based genomic profiling serves as a robust tool in the genetic diagnosis of ALL, outreaching conventional karyotyping in CNA detection both in terms of sensitivity and specificity. We also propose a practical workflow for a comprehensive and objective interpretation of CNAs obtained through microarray-based genomic profiling, thereby facilitating its application in a routine clinical diagnostic setting.


Assuntos
Análise de Sequência com Séries de Oligonucleotídeos/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Criança , Aberrações Cromossômicas , Impressões Digitais de DNA/métodos , Feminino , Dosagem de Genes , Humanos , Hibridização in Situ Fluorescente/métodos , Cariotipagem/métodos , Masculino , Polimorfismo de Nucleotídeo Único , Sensibilidade e Especificidade
18.
Blood Cancer Discov ; 3(1): 16-31, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35019858

RESUMO

Central nervous system (CNS) dissemination of B-precursor acute lymphoblastic leukemia (B-ALL) has poor prognosis and remains a therapeutic challenge. Here we performed targeted DNA sequencing as well as transcriptional and proteomic profiling of paired leukemia-infiltrating cells in the bone marrow (BM) and CNS of xenografts. Genes governing mRNA translation were upregulated in CNS leukemia, and subclonal genetic profiling confirmed this in both BM-concordant and BM-discordant CNS mutational populations. CNS leukemia cells were exquisitely sensitive to the translation inhibitor omacetaxine mepesuccinate, which reduced xenograft leptomeningeal disease burden. Proteomics demonstrated greater abundance of secreted proteins in CNS-infiltrating cells, including complement component 3 (C3), and drug targeting of C3 influenced CNS disease in xenografts. CNS-infiltrating cells also exhibited selection for stemness traits and metabolic reprogramming. Overall, our study identifies targeting of mRNA translation as a potential therapeutic approach for B-ALL leptomeningeal disease. SIGNIFICANCE: Cancer metastases are often driven by distinct subclones with unique biological properties. Here we show that in B-ALL CNS disease, the leptomeningeal environment selects for cells with unique functional dependencies. Pharmacologic inhibition of mRNA translation signaling treats CNS disease and offers a new therapeutic approach for this condition.This article is highlighted in the In This Issue feature, p. 1.


Assuntos
Doenças do Sistema Nervoso Central , Neoplasias do Sistema Nervoso Central , Neoplasias Meníngeas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Sistema Nervoso Central/metabolismo , Doenças do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Humanos , Neoplasias Meníngeas/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Biossíntese de Proteínas/genética , Proteômica
19.
J Clin Oncol ; 40(17): 1892-1902, 2022 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-35230882

RESUMO

PURPOSE: Wilms tumor (WT) is associated with (epi)genetic predisposing factors affecting a growing number of WT predisposing genes and loci, including those causing Beckwith-Wiedemann spectrum (BWSp) or WT1-related syndromes. To guide genetic counseling and testing, we need insight into the prevalence of WT predisposing (epi)genetic factors. PATIENTS AND METHODS: All children diagnosed with WT in the Netherlands between 2015 and 2020 were referred to a clinical geneticist. Phenotypic data, disease characteristics, and diagnostic test results were collected. If no genetic predisposition was identified by targeted diagnostic testing, germline (trio-)whole-exome sequencing and BWSp testing on normal kidney-derived DNA were offered. RESULTS: A total of 126 cases were analyzed of 128 identified patients. (Epi)genetic predisposing factors were present in 42 of 126 patients (33.3%) on the basis of a molecular diagnosis in blood-derived DNA (n = 26), normal kidney-derived DNA (n = 12), or solely a clinical diagnosis of BWSp (n = 4). Constitutional, heterozygous DIS3L2 variants were identified as a recurrent predisposing factor in five patients (4%), with a second somatic hit in 4 of 5 tumors. Twenty patients (16%) were diagnosed with BWSp while four additional patients without BWSp features harbored chromosome 11p15 methylation defects in normal kidney tissue. Remaining findings included WT1-related syndromes (n = 10), Fanconi anemia (n = 1), neurofibromatosis type 1 (n = 1), and a pathogenic REST variant (n = 1). In addition, (likely) pathogenic variants in adult-onset cancer predisposition genes (BRCA2, PMS2, CHEK2, and MUTYH) were identified in 5 of 56 (8.9%) patients with available whole-exome sequencing data. Several candidate WT predisposition genes were identified, which require further validation. CONCLUSION: (Epi)genetic WT predisposing factors, including mosaic aberrations and recurrent heterozygous DIS3L2 variants, were present in at least 33.3% of patients with WT. On the basis of these results, we encourage standard genetic testing after counseling by a clinical geneticist.


Assuntos
Síndrome de Beckwith-Wiedemann , Neoplasias Renais , Tumor de Wilms , Adulto , Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/genética , Síndrome de Beckwith-Wiedemann/patologia , Causalidade , Criança , Predisposição Genética para Doença , Genômica , Mutação em Linhagem Germinativa , Humanos , Neoplasias Renais/epidemiologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Prevalência , Tumor de Wilms/epidemiologia , Tumor de Wilms/genética , Tumor de Wilms/patologia
20.
Eur J Cancer ; 175: 311-325, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36182817

RESUMO

iTHER is a Dutch prospective national precision oncology program aiming to define tumour molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory paediatric tumours. Between April 2017 and April 2021, 302 samples from 253 patients were included. Comprehensive molecular profiling including low-coverage whole genome sequencing (lcWGS), whole exome sequencing (WES), RNA sequencing (RNA-seq), Affymetrix, and/or 850k methylation profiling was successfully performed for 226 samples with at least 20% tumour content. Germline pathogenic variants were identified in 16% of patients (35/219), of which 22 variants were judged causative for a cancer predisposition syndrome. At least one somatic alteration was detected in 204 (90.3%), and 185 (81.9%) were considered druggable, with clinical priority very high (6.1%), high (21.3%), moderate (26.0%), intermediate (36.1%), and borderline (10.5%) priority. iTHER led to revision or refinement of diagnosis in 8 patients (3.5%). Temporal heterogeneity was observed in paired samples of 15 patients, indicating the value of sequential analyses. Of 137 patients with follow-up beyond twelve months, 21 molecularly matched treatments were applied in 19 patients (13.9%), with clinical benefit in few. Most relevant barriers to not applying targeted therapies included poor performance status, as well as limited access to drugs within clinical trial. iTHER demonstrates the feasibility of comprehensive molecular profiling across all ages, tumour types and stages in paediatric cancers, informing of diagnostic, prognostic, and targetable alterations as well as reportable germline variants. Therefore, WES and RNA-seq is nowadays standard clinical care at the Princess Máxima Center for all children with cancer, including patients at primary diagnosis. Improved access to innovative treatments within biology-driven combination trials is required to ultimately improve survival.


Assuntos
Neoplasias , Adolescente , Criança , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Oncologia , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Medicina de Precisão , Estudos Prospectivos , Sequenciamento do Exoma
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