RESUMO
The discovery of novel hematopoietic stem cell (HSC) surface markers can enhance understanding of HSC identity and function. We have discovered a population of primitive bone marrow (BM) HSCs distinguished by their expression of the heparan sulfate proteoglycan Syndecan-2, which serves as both a marker and a regulator of HSC function. Syndecan-2 expression was increased 10-fold in CD150+CD48-CD34-c-Kit+Sca-1+Lineage- cells (long-term HSCs [LT-HSCs]) compared with differentiated hematopoietic cells. Isolation of BM cells based solely on syndecan-2 surface expression produced a 24-fold enrichment for LT-HSCs and sixfold enrichment for α-catulin+c-kit+ HSCs, and yielded HSCs with superior in vivo repopulating capacity compared with CD150+ cells. Competitive repopulation assays revealed the HSC frequency to be 17-fold higher in syndecan-2+CD34-KSL cells compared with syndecan-2-CD34-KSL cells and indistinguishable from CD150+CD34-KSL cells. Syndecan-2 expression also identified nearly all repopulating HSCs within the CD150+CD34-KSL population. Mechanistically, syndecan-2 regulates HSC repopulating capacity through control of expression of Cdkn1c (p57) and HSC quiescence. Loss of syndecan-2 expression caused increased HSC cell cycle entry, downregulation of Cdkn1c, and loss of HSC long-term repopulating capacity. Syndecan-2 is a novel marker of HSCs that regulates HSC repopulating capacity via control of HSC quiescence.
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Células-Tronco Hematopoéticas/citologia , Sindecana-2/metabolismo , Animais , Ciclo Celular , Diferenciação Celular , Células Cultivadas , Feminino , Regulação da Expressão Gênica , Células-Tronco Hematopoéticas/metabolismo , Masculino , Camundongos , Sindecana-2/genéticaRESUMO
Cardiovascular diseases remain a leading cause of hospitalization affecting approximately 38 million people worldwide. While pharmacological and revascularization techniques can improve the patient's survival and quality of life, they cannot help reversing myocardial infarction injury and heart failure. Direct reprogramming of somatic cells to cardiomyocyte and cardiac progenitor cells offers a new approach to cellular reprogramming and paves the way for translational regenerative medicine. Direct reprogramming can bypass the pluripotent stage with the potential advantage of non-immunogenic cell products, reduced carcinogenic risk, and no requirement for embryonic tissue. The process of directly reprogramming cardiac cells was first achieved through the overexpression of transcription factors such as GATA4, MEF2C, and TBX5. However, over the past decade, significant work has been focused on enhancing direct reprogramming using a mixture of transcription factors, microRNAs, and small molecules to achieve cardiac cell fate. This review discusses the evolution of direct reprogramming, recent progress in achieving efficient cardiac cell fate conversion, and describes the reprogramming mechanisms at a molecular level. We also explore various viral and non-viral delivery methods currently being used to aid in the delivery of reprogramming factors to improve efficiency. However, further studies will be needed to overcome molecular and epigenetic barriers to successfully achieve translational cardiac regenerative therapeutics.
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Técnicas de Reprogramação Celular , Qualidade de Vida , Humanos , Técnicas de Reprogramação Celular/métodos , Miócitos Cardíacos , Reprogramação Celular , Fatores de Transcrição/genética , Medicina Regenerativa/métodos , FibroblastosRESUMO
Crouzon Syndrome is a genetic craniosynostosis disorder associated with a high risk of ophthalmologic sequelae secondary to structural causes. However, ophthalmologic disorders due to intrinsic nerve aberrations in Crouzon Syndrome have not been described. Optic pathway gliomas (OPGs) are low grade gliomas that are intrinsic to the visual pathway, frequently associated with Neurofibromatosis type 1 (NF-1). OPGs involving both optic nerves without affecting the optic chiasm are rarely seen outside of NF-1. We report an unusual case of bilateral optic nerve glioma without chiasmatic involvement in a 17-month-old male patient with Crouzon Syndrome without any clinical or genetic findings of NF-1. This case suggests that close ophthalmologic follow up and orbital MRIs may benefit patients with Crouzon Syndrome.
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Disostose Craniofacial , Neurofibromatose 1 , Glioma do Nervo Óptico , Neoplasias do Nervo Óptico , Humanos , Masculino , Lactente , Glioma do Nervo Óptico/complicações , Vias Visuais , Neoplasias do Nervo Óptico/complicações , Disostose Craniofacial/complicaçõesRESUMO
PURPOSE: This study aimed to describe the spectrum of cancers observed in Bloom Syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome as these are not well-defined. METHODS: Data from the Bloom Syndrome Registry (BSR) was used for this study. Cancer history, ages of first cancer diagnosis, and ages of death were compiled from the BSR and analyzed. RESULTS: Among the 290 individuals in the BSR, 155 (53%) participants developed 251 malignant neoplasms; 100 (65%) were diagnosed with 1 malignancy, whereas the remaining 55 (35%) developed multiple malignancies. Of the 251 neoplasms, 83 (33%) were hematologic and 168 (67%) were solid tumors. Hematologic malignancies (leukemia and lymphoma) were more common than any of the solid tumors. The most commonly observed solid tumors were colorectal, breast, and oropharyngeal. The cumulative incidence of any malignancy by age 40 was 83%. The median survival for all participants in the BSR was 36.2 years. There were no significant differences in time to first cancer diagnosis or survival by genotype among the study participants. CONCLUSION: We describe the spectrum of cancers observed in Bloom syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome. We also highlight the significant differences in survival and age of diagnosis seen among different tumor types and genotypes.
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Síndrome de Bloom , Neoplasias Hematológicas , Neoplasias , Adulto , Síndrome de Bloom/diagnóstico , Síndrome de Bloom/epidemiologia , Síndrome de Bloom/genética , Neoplasias Hematológicas/diagnóstico , Humanos , Incidência , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Sistema de RegistrosRESUMO
Chemotherapy and irradiation cause DNA damage to hematopoietic stem cells (HSCs), leading to HSC depletion and dysfunction and the risk of malignant transformation over time. Extrinsic regulation of HSC DNA repair is not well understood, and therapies to augment HSC DNA repair following myelosuppression remain undeveloped. We report that epidermal growth factor receptor (EGFR) regulates DNA repair in HSCs following irradiation via activation of the DNA-dependent protein kinase-catalytic subunit (DNA-PKcs) and nonhomologous end joining (NHEJ). We show that hematopoietic regeneration in vivo following total body irradiation is dependent upon EGFR-mediated repair of DNA damage via activation of DNA-PKcs. Conditional deletion of EGFR in hematopoietic stem and progenitor cells (HSPCs) significantly decreased DNA-PKcs activity following irradiation, causing increased HSC DNA damage and depressed HSC recovery over time. Systemic administration of epidermal growth factor (EGF) promoted HSC DNA repair and rapid hematologic recovery in chemotherapy-treated mice and had no effect on acute myeloid leukemia growth in vivo. Further, EGF treatment drove the recovery of human HSCs capable of multilineage in vivo repopulation following radiation injury. Whole-genome sequencing analysis revealed no increase in coding region mutations in HSPCs from EGF-treated mice, but increased intergenic copy number variant mutations were detected. These studies demonstrate that EGF promotes HSC DNA repair and hematopoietic regeneration in vivo via augmentation of NHEJ. EGF has therapeutic potential to promote human hematopoietic regeneration, and further studies are warranted to assess long-term hematopoietic effects.
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Reparo do DNA por Junção de Extremidades , Receptores ErbB/metabolismo , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/metabolismo , Regeneração , Animais , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Dano ao DNA , Proteína Quinase Ativada por DNA/genética , Proteína Quinase Ativada por DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fator de Crescimento Epidérmico/genética , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/genética , Células-Tronco Hematopoéticas/citologia , Humanos , CamundongosRESUMO
Activating variants in the platelet-derived growth factor receptor ß gene (PDGFRB) have been associated with Kosaki overgrowth syndrome, infantile myofibromatosis, and Penttinen premature aging syndrome. A recently described phenotype with fusiform aneurysm has been associated with mosaic PDGFRB c.1685A > G p.(Tyr562Cys) variant. Few reports however have examined the vascular phenotypes and mosaic effects of PDGFRB variants. We describe clinical characteristics of two patients with a recurrent mosaic PDGFRB p.(Tyr562Cys) variant identified via next-generation sequencing-based genetic testing. We observed intracranial fusiform aneurysm in one patient and found an additional eight patients with aneurysms and phenotypes associated with PDGFRB-activating variants through literature search. The conditions caused by PDGFRB-activating variants share overlapping features including overgrowth, premature aged skin, and vascular malformations including aneurysms. Aneurysms are progressive and can result in morbidities and mortalities in the absence of successful intervention. Germline and/or somatic testing for PDGFRB gene should be obtained when PDGFRB activating variant-related phenotypes are present. Whole-body imaging of the arterial tree and echocardiography are recommended after diagnosis. Repeating the imaging study within a 6- to 12-month period after detection is reasonable. Finally, further evaluation for the effectiveness and safety profile of kinase inhibitors in this patient population is warranted.
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Aneurisma/genética , Transtornos do Crescimento/genética , Aneurisma Intracraniano/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Adulto , Senilidade Prematura/genética , Aneurisma/epidemiologia , Aneurisma/patologia , Criança , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Transtornos do Crescimento/epidemiologia , Transtornos do Crescimento/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Aneurisma Intracraniano/epidemiologia , Aneurisma Intracraniano/patologia , Masculino , Pessoa de Meia-Idade , Mosaicismo , Fenótipo , Anormalidades da Pele/epidemiologia , Anormalidades da Pele/genética , Anormalidades da Pele/patologia , Adulto JovemRESUMO
Hodgkin lymphoma (HL) is a highly curable form of cancer, and current treatment regimens are focused on improving treatment efficacy while decreasing the risk of late effects of treatment. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for pediatric HL provide recommendations on the workup, diagnostic evaluation, and treatment of classic HL, including principles of pathology, imaging, staging, systemic therapy, and radiation therapy. This portion of the NCCN Guidelines focuses on the management of pediatric classic HL in the upfront and relapsed/refractory settings.
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Doença de Hodgkin , Criança , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/patologia , Doença de Hodgkin/terapia , Humanos , Oncologia , Resultado do TratamentoRESUMO
PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. CONCLUSION: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.
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Fator de Ligação a CCCTC/genética , Fator de Ligação a CCCTC/metabolismo , Transtornos do Neurodesenvolvimento/genética , Animais , Criança , Cromatina/genética , Cromatina/metabolismo , Deficiências do Desenvolvimento/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Humanos , Deficiência Intelectual/genética , Masculino , Mutação/genética , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/metabolismo , Fatores de Transcrição/genética , Sequenciamento do Exoma/métodos , Adulto JovemRESUMO
The hedgehog (Hh) pathway is highly conserved and required for embryonic patterning and determination. Mutations in the Hh pathway are observed in sporadic tumors as well as under syndromic conditions. Common to these syndromes are the findings of polydactyly/syndactyly and brain overgrowth. The latter is also a finding most commonly observed in the cases of mutations in the PI3K/AKT/mTOR pathway. We have identified novel Hh pathway mutations and structural copy number variations in individuals with somatic overgrowth, macrocephaly, dysmorphic facial features, and developmental delay, which phenotypically closely resemble patients with phosphatase and tensin homolog (PTEN) mutations. We hypothesized that brain overgrowth and phenotypic overlap with syndromic overgrowth syndromes in these cases may be due to crosstalk between the Hh and PI3K/AKT/mTOR pathways. To test this, we modeled disease-associated variants by generating PTCH1 and Suppressor of Fused (SUFU) heterozygote cell lines using the CRISPR/Cas9 system. These cells demonstrate activation of PI3K signaling and increased phosphorylation of its downstream target p4EBP1 as well as a distinct cellular phenotype. To further investigate the mechanism underlying this crosstalk, we treated human neural stem cells with sonic hedgehog (SHH) ligand and performed transcriptional analysis of components of the mTOR pathway. These studies identified decreased expression of a set of mTOR negative regulators, leading to its activation. We conclude that there is a significant crosstalk between the SHH and PI3K/AKT/mTOR. We propose that this crosstalk is responsible for why mutations in PTCH1 and SUFU lead to macrocephaly phenotypes similar to those observed in PTEN hamartoma and other overgrowth syndromes associated with mutations in PI3K/AKT/mTOR pathway genes.
Assuntos
Proteínas Hedgehog/metabolismo , Megalencefalia/genética , Megalencefalia/metabolismo , Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Sistemas CRISPR-Cas , Linhagem Celular , Pré-Escolar , Feminino , Deleção de Genes , Haploinsuficiência , Humanos , Lactente , Masculino , Megalencefalia/diagnóstico , Modelos Biológicos , Células-Tronco NeuraisRESUMO
PURPOSE OF REVIEW: The goal of this review is to summarize current understanding of pharmacogenetics and pharmacogenomics in chemotherapy-induced cardiotoxicity. RECENT FINDINGS: Most of the studies rely on in vitro cytotoxic assays. There have been several smaller scale candidate gene approaches and a handful of genome-wide studies linking genetic variation to susceptibility to chemotherapy-induced cardiotoxicity. Currently, pharmacogenomic testing of all childhood cancer patients with an indication for doxorubicin or daunorubicin therapy for RARG rs2229774, SLC28A3 rs7853758, and UGT1A6*4 rs17863783 variants is recommended. There is no recommendation regarding testing in adults. There is clear evidence pointing to the role of pharmacogenetics and pharmacogenomics in cardiotoxicity susceptibility to chemotherapeutic agents. Larger scale studies are needed to further identify susceptibility markers and to develop pharmacogenomics-based risk profiling to improve quality of life and life expectancy in cancer survivors.
Assuntos
Antineoplásicos/efeitos adversos , Cardiotoxicidade/genética , Farmacogenética/métodos , Animais , Antineoplásicos/uso terapêutico , Cardiotoxicidade/etiologia , Daunorrubicina/efeitos adversos , Daunorrubicina/farmacologia , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Testes Genéticos , Humanos , Camundongos , Polimorfismo de Nucleotídeo Único , Receptores do Ácido Retinoico/genética , Receptor gama de Ácido RetinoicoRESUMO
Adolescent brothers were diagnosed with testicular germ cell tumors within the same month. Both were found to have multiple renal cysts on pretreatment imaging done for staging. The proband, his brother, and their mother, were all found to have a novel splice variant in intron 8 of the PKD1 gene by clinical exome sequencing. This is the second family reported with both familial testicular germ cell tumor (FTGCT) and autosomal dominant polycystic kidney disease (ADPKD), and the first described association of FTGCT with a splice variant in PKD1. We suggest that this novel variant in PKD1 may convey increased risk for FTGCT in addition to causing ADPKD.
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Mutação/genética , Neoplasias Embrionárias de Células Germinativas/genética , Rim Policístico Autossômico Dominante/genética , Canais de Cátion TRPP/genética , Neoplasias Testiculares/genética , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/complicações , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Linhagem , Fenótipo , Rim Policístico Autossômico Dominante/complicações , Rim Policístico Autossômico Dominante/tratamento farmacológico , Prognóstico , Neoplasias Testiculares/complicações , Neoplasias Testiculares/tratamento farmacológicoAssuntos
Neoplasias Cerebelares/genética , Cromograninas/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Mutação em Linhagem Germinativa , Proteínas Hedgehog/metabolismo , Meduloblastoma/genética , Neoplasias Cerebelares/patologia , Feminino , Proteínas Hedgehog/genética , Humanos , Lactente , Masculino , Meduloblastoma/patologia , Linhagem , PrognósticoRESUMO
IMPORTANCE: Clinical exome sequencing (CES) is rapidly becoming a common molecular diagnostic test for individuals with rare genetic disorders. OBJECTIVE: To report on initial clinical indications for CES referrals and molecular diagnostic rates for different indications and for different test types. DESIGN, SETTING, AND PARTICIPANTS: Clinical exome sequencing was performed on 814 consecutive patients with undiagnosed, suspected genetic conditions at the University of California, Los Angeles, Clinical Genomics Center between January 2012 and August 2014. Clinical exome sequencing was conducted as trio-CES (both parents and their affected child sequenced simultaneously) to effectively detect de novo and compound heterozygous variants or as proband-CES (only the affected individual sequenced) when parental samples were not available. MAIN OUTCOMES AND MEASURES: Clinical indications for CES requests, molecular diagnostic rates of CES overall and for phenotypic subgroups, and differences in molecular diagnostic rates between trio-CES and proband-CES. RESULTS: Of the 814 cases, the overall molecular diagnosis rate was 26% (213 of 814; 95% CI, 23%-29%). The molecular diagnosis rate for trio-CES was 31% (127 of 410 cases; 95% CI, 27%-36%) and 22% (74 of 338 cases; 95% CI, 18%-27%) for proband-CES. In cases of developmental delay in children (<5 years, n = 138), the molecular diagnosis rate was 41% (45 of 109; 95% CI, 32%-51%) for trio-CES cases and 9% (2 of 23, 95% CI, 1%-28%) for proband-CES cases. The significantly higher diagnostic yield (P value = .002; odds ratio, 7.4 [95% CI, 1.6-33.1]) of trio-CES was due to the identification of de novo and compound heterozygous variants. CONCLUSIONS AND RELEVANCE: In this sample of patients with undiagnosed, suspected genetic conditions, trio-CES was associated with higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods. Additional studies designed to validate these findings and to explore the effect of this approach on clinical and economic outcomes are warranted.
Assuntos
Exoma , Doenças Genéticas Inatas/diagnóstico , Técnicas de Diagnóstico Molecular , Doenças Raras/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Doenças Raras/genética , Análise de Sequência de DNA/métodosRESUMO
Hematopoietic aging is associated with decreased hematopoietic stem cell (HSC) self-renewal capacity and myeloid skewing. We report that culture of bone marrow (BM) HSCs from aged mice with epidermal growth factor (EGF) suppressed myeloid skewing, increased multipotent colony formation, and increased HSC repopulation in primary and secondary transplantation assays. Mice transplanted with aged, EGF-treated HSCs displayed increased donor cell engraftment within BM HSCs and systemic administration of EGF to aged mice increased HSC self-renewal capacity in primary and secondary transplantation assays. Expression of a dominant negative EGFR in Scl/Tal1+ hematopoietic cells caused increased myeloid skewing and depletion of long term-HSCs in 15-month-old mice. EGF treatment decreased DNA damage in aged HSCs and shifted the transcriptome of aged HSCs from genes regulating cell death to genes involved in HSC self-renewal and DNA repair but had no effect on HSC senescence. These data suggest that EGFR signaling regulates the repopulating capacity of aged HSCs.
RESUMO
Children with certain germline gene variants have an increased risk of developing myelodysplastic syndrome (MDS) and other hematopoietic malignancies (HM), such as leukemias and lymphomas. Recent studies have identified an expanding number of these predisposition genes, with variants most prevalent in children with MDS but also found in other HM. For some hematopoietic malignancy predisposition (HMP) disorders, specifically those with a high risk of MDS, early intervention through hematopoietic stem cell transplantation (HSCT) can favorably impact overall survival, providing a rationale for rigorous surveillance. A multidisciplinary panel of experts at the 2023 AACR Childhood Cancer Predisposition Workshop reviewed the latest advances in the field and updated prior 2017 surveillance recommendations for children with HMP. In addition to general guidance for all children with HMP, which includes annual physical examination, education about the signs and symptoms of HM, consultation with experienced providers, and early assessment by an HSCT specialist, the panel provided specific recommendations for individuals with a higher risk of MDS based on the affected gene. These recommendations include periodic and comprehensive surveillance for individuals with those syndromes associated with higher risk of MDS, including serial bone marrow examinations to monitor for morphologic changes and deep sequencing for somatic changes in genes associated with HM progression. This approach enables close monitoring of disease evolution based on the individual's genetic profile. As more HMP-related genes are discovered and the disorders' natural histories are better defined, these personalized recommendations will serve as a foundation for future guidelines in managing these conditions.
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BACKGROUND: Acute lymphoblastic leukemia (ALL) diagnosed within the first month of life is classified as congenital ALL and has a significantly worse outcome than ALL diagnosed in older children. This suggests that congenital ALL is a biologically different disease, and thus may be caused by a distinct set of mutations. To understand the somatic and germline mutations contributing to congenital ALL, the protein-coding regions in the genome were captured and whole-exome sequencing was employed for the identification of single-nucleotide variants and small insertion and deletions in the germlines as well as the primary tumors of four patients with congenital ALL. METHODS: Exome sequencing was performed on Illumina GAIIx or HiSeq 2000 (Illumina, San Diego, California). Reads were aligned to the human reference genome and the Genome Analysis Toolkit was used for variant calling. An in-house developed Ensembl-based variant annotator was used to richly annotate each variant. RESULTS: There were 1-3 somatic, protein-damaging mutations per ALL, including a novel mutation in Sonic Hedgehog. Additionally, there were many germline mutations in genes known to be associated with cancer predisposition, as well as genes involved in DNA repair. CONCLUSION: This study is the first to comprehensively characterize the germline and somatic mutational profile of all protein-coding genes patients with congenital ALL. These findings identify potentially important therapeutic targets, as well as insight into possible cancer predisposition genes.
Assuntos
Análise Mutacional de DNA , Exoma , Mutação em Linhagem Germinativa , Mutagênese Insercional , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Deleção de Sequência , Estudos de Casos e Controles , Bases de Dados Genéticas , Predisposição Genética para Doença , Genoma Humano , Humanos , Lactente , Recém-Nascido , Leucemia-Linfoma Linfoblástico de Células Precursoras/congênitoRESUMO
BACKGROUND: Gastric adenocarcinoma is a rare diagnosis in childhood. A 14-year-old male patient presented with metastatic gastric adenocarcinoma, and a strong family history of colon cancer. Clinical sequencing of CDH1 and APC were negative. Whole exome sequencing was therefore applied to capture the majority of protein-coding regions for the identification of single-nucleotide variants, small insertion/deletions, and copy number abnormalities in the patient's germline as well as primary tumor. MATERIALS AND METHODS: DNA was extracted from the patient's blood, primary tumor, and the unaffected mother's blood. DNA libraries were constructed and sequenced on Illumina HiSeq2000. Data were post-processed using Picard and Samtools, then analyzed with the Genome Analysis Toolkit. Variants were annotated using an in-house Ensembl-based program. Copy number was assessed using ExomeCNV. RESULTS: Each sample was sequenced to a mean depth of coverage of greater than 120×. A rare non-synonymous coding single-nucleotide variant (SNV) in TP53 was identified in the germline. There were 10 somatic cancer protein-damaging variants that were not observed in the unaffected mother genome. ExomeCNV comparing tumor to the patient's germline, identified abnormal copy number, spanning 6,946 genes. CONCLUSION: We present an unusual case of Li-Fraumeni detected by whole exome sequencing. There were also likely driver somatic mutations in the gastric adenocarcinoma. These results highlight the need for more thorough and broad scale germline and cancer analyses to accurately inform patients of inherited risk to cancer and to identify somatic mutations.
Assuntos
Adenocarcinoma/genética , Predisposição Genética para Doença/genética , Síndrome de Li-Fraumeni/genética , Neoplasias Gástricas/genética , Proteína Supressora de Tumor p53/genética , Adolescente , Análise Mutacional de DNA , Exoma/genética , Dosagem de Genes , Mutação em Linhagem Germinativa , Humanos , Síndrome de Li-Fraumeni/complicações , Masculino , Linhagem , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Letters of recommendation are ubiquitous in the research enterprise. Requesting, writing, and reviewing letters of recommendation are all fraught with bias, especially for individuals from groups historically excluded from research environments. We detail how letter reviewers, requesters, and writers can make letters of recommendation a more equitable tool to evaluate scientists.
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Internato e Residência , Humanos , RedaçãoRESUMO
BACKGROUND: While there are many epidemiologic studies of Asian immigrants to the West and risk of inflammatory bowel disease (IBD), the phenotype and lifestyle of Asian patients, particularly children, with IBD are not well described. In this study, we describe lifestyle practices, such as dietary pattern, as well as disease phenotype in Asian American children with IBD. METHODS: We reviewed the records of children with IBD, ages 0 to 21 years old, and race identified as Asian, Indian, or Pacific Islander. Patients who received outpatient IBD care at our center between January 2013 and January 2020 were included. We excluded patients who were international second opinions, who did not have a definitive diagnosis of IBD, and in whom a diagnosis of IBD was made after 18 years of age. A survey, including a food frequency questionnaire adapted from NHANES DSQ with modifications to include culturally appropriate food elements, was designed and conducted within this cohort to assess for dietary patterns. RESULTS: Asian patients in our cohort have similar phenotypes as non-Asians with few distinctive differences. There was a Crohn's disease and male predominance similar with non-Asians. However, there was a high rate of proctitis in ulcerative colitis in Asian patients. Asian patients reported a typical dietary pattern that reflects a Westernized pattern rather than a traditional pattern. Despite a similar dietary pattern, there was a high rate of 25-OH Vitamin D deficiency (44%) and insufficiency (40%). CONCLUSIONS: This single center study showed that the phenotype of Asian children with IBD in the U.S. is similar with that of non-Asian with a few distinct differences. The Asian children in our cohort reported following a Westernized dietary pattern and lifestyle. However, there was a high rate of Vitamin D deficiency surrounding diagnosis, suggesting a need for vigilant monitoring.