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In Fig. 3c of this Letter, the the effects of CRISPR-Cas9-mediated deletion of NR3C1, TXNIP and CNR2 in patient-derived B-lineage leukaemia cells were shown. For curves depicting NR3C1 (left graph), data s for TXNIP (middle graph) were inadvertently plotted. This figure has been corrected online, and the original Fig. 3c is shown as Supplementary Information to this Amendment for transparency. The error does not affect the conclusions of the Letter. In addition, Source Data files have been added for the Figs. 1-4 and Extended Data Figs. 1-10 of the original Letter.
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B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development, yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL). The importance of these lesions in ALL has, until now, remained unclear. Here, by combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, we identify a novel B-lymphoid program for transcriptional repression of glucose and energy supply. Our metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy deprivation, resulting in constitutive activation of the energy-stress sensor AMPK. Dominant-negative mutants of PAX5 and IKZF1, however, relieved this glucose and energy restriction. In a transgenic pre-B ALL mouse model, the heterozygous deletion of Pax5 increased glucose uptake and ATP levels by more than 25-fold. Reconstitution of PAX5 and IKZF1 in samples from patients with pre-B ALL restored a non-permissive state and induced energy crisis and cell death. A CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets identified the products of NR3C1 (encoding the glucocorticoid receptor), TXNIP (encoding a glucose-feedback sensor) and CNR2 (encoding a cannabinoid receptor) as central effectors of B-lymphoid restriction of glucose and energy supply. Notably, transport-independent lipophilic methyl-conjugates of pyruvate and tricarboxylic acid cycle metabolites bypassed the gatekeeper function of PAX5 and IKZF1 and readily enabled leukaemic transformation. Conversely, pharmacological TXNIP and CNR2 agonists and a small-molecule AMPK inhibitor strongly synergized with glucocorticoids, identifying TXNIP, CNR2 and AMPK as potential therapeutic targets. Furthermore, our results provide a mechanistic explanation for the empirical finding that glucocorticoids are effective in the treatment of B-lymphoid but not myeloid malignancies. Thus, B-lymphoid transcription factors function as metabolic gatekeepers by limiting the amount of cellular ATP to levels that are insufficient for malignant transformation.
Assuntos
Linfócitos B/metabolismo , Metabolismo Energético/genética , Regulação Neoplásica da Expressão Gênica , Glucose/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Fatores de Transcrição/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Animais , Linfócitos B/efeitos dos fármacos , Carcinogênese/genética , Proteínas de Transporte/agonistas , Proteínas de Transporte/metabolismo , Morte Celular , Imunoprecipitação da Cromatina , Ciclo do Ácido Cítrico , Modelos Animais de Doenças , Feminino , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Fator de Transcrição Ikaros/metabolismo , Camundongos , Camundongos Transgênicos , Fator de Transcrição PAX5/deficiência , Fator de Transcrição PAX5/genética , Fator de Transcrição PAX5/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Ácido Pirúvico/metabolismo , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/metabolismo , Receptores de Glucocorticoides/metabolismo , Análise de Sequência de RNARESUMO
The new genetics, defined as that which followed the completion of the human genome project and includes development of rapid and cheaper next-generation sequencing (NGS), is impacting our medical world in several ways (1). As is the case in any new area of medicine, the field is infused with "truthiness," where instead, what is needed for good patient care and scientific rigor is an effort to close in on the truth. Today, I'll discuss how variation in the human genome is being evaluated and re-evaluated as we sequence more and more of our patients' genes.
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Aconselhamento Genético/métodos , Testes Genéticos/métodos , Variação Genética , Genoma Humano , Neoplasias/genética , Revelação da Verdade , Predisposição Genética para Doença , Hereditariedade , Humanos , Neoplasias/patologia , Neoplasias/terapia , Educação de Pacientes como Assunto , Linhagem , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Fatores de RiscoRESUMO
Importance: Variant reclassification is an important component of hereditary cancer genetic testing; however, there are few published data quantifying the prevalence of reclassification. Objective: Retrospective cohort study of individuals who had genetic testing from 2006 through 2016 at a single commercial laboratory. Design, Setting, and Participants: A retrospective cohort of individuals who had genetic testing between 2006 and 2016 at a single commercial laboratory was assessed. Variants were classified as benign, likely benign, variant of uncertain significance, likely pathogenic, or pathogenic. Retrospective chart reviews were conducted for patients from the University of Texas Southwestern (UTSW) Medical Center. Exposures: Hereditary cancer genetic testing. Main Outcomes and Measures: Frequency of and time to amended reports; frequency and types of variant reclassification. Results: From 2006 through 2018, 1.45 million individuals (median [interquartile range] age at testing, 49 years [40.69-58.31 years], 95.6% women) had genetic testing, and 56.6% (n = 821â¯724) had a personal history of cancer. A total of 1.67 million initial tests were reported and 59â¯955 amended reports were issued due to variant reclassification. Overall, 6.4% (2868 of 44â¯777) of unique variants were reclassified. Reclassification to a different clinical category was rare among unique variants initially classified as pathogenic or likely pathogenic (0.7%, 61 of 9112) or benign or likely benign (0.2%, 15 of 8995). However, 7.7% (2048 of 26â¯670) of unique variants of uncertain significance were reclassified: 91.2% (1867 of 2048) were downgraded to benign or likely benign (median time to amended report, 1.17 years), 8.7% (178 of 2048) were upgraded to pathogenic or likely pathogenic variants (median time to amended report, 1.86 years). Because most variants were observed in more than 1 individual, 24.9% (46â¯890 of 184â¯327) of all reported variants of uncertain significance were reclassified. Conclusions and Relevance: Following hereditary cancer genetic testing at a single commercial laboratory, 24.9% of variants of uncertain significance were reclassified, which included both downgrades and upgrades. Further research is needed to assess generalizability of the findings for other laboratories, as well as the clinical consequences of the reclassification as a component of a genetic testing program.
Assuntos
Predisposição Genética para Doença , Testes Genéticos , Variação Genética , Neoplasias/genética , Adulto , Feminino , Doenças Genéticas Inatas/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos RetrospectivosRESUMO
This study explores the potential impact of the genetic counseling assistant (GCA) position on the efficiency of the genetic counseling field, evaluates attitudes regarding expansion of the genetic counseling field to include the GCA, and presents data on GCA endeavors and GCA job tasks as reported by GCAs, certified genetic counselors (CGCs), and program directors (PDs). Data on GCA roles and attitudes toward different aspects of the GCA position were collected via surveys of CGCs who have worked with GCAs, PDs who have and have not had experience with GCAs in their programs, and GCAs. We analyzed responses from 63 individuals: 27 PDs, 22 CGCs, and 14 GCAs. GCAs' impact on efficiency was calculated via internal analysis of genetic patient volume per genetic counselor within the University of Texas Southwestern (UTSW) patient database prior to, and since the addition of, a GCA to the practice. The response rates for PDs, CGCs, and GCAs were 27 %, 79 %, and 61 %, respectively. Every CGC stated the GCA increased their efficiency. CGCs with a GCA reported a 60 % average increase in patient volume. This figure was congruent with internal data from the UTSW cancer genetics program (58.5 % increase). Appropriate responsibilities for GCAs as reported by CGCs and PDs (>90 %) include: data entry, shipping tests, administrative tasks, research, and ordering supplies. Regarding GCAs delivering test results, there was response variation whether this should be a job duty: 42 % of CGCs agreed to GCAs delivering negative results to patients, compared to 22 % of program directors. Twenty-two percent of PDs expressed concern about the job title "Genetic Counseling Assistant." Ninety percent of CGCs felt that GCA was a career path to becoming a CGC, compared to 42 % of PDs. Eighty-three percent of GCAs who decided to apply to CGC graduate programs were accepted. We conclude the addition of a GCA to a genetic counseling practice contributes to increased efficiency and is one way to expand the reach of the profession.
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Pessoal Técnico de Saúde/organização & administração , Atitude do Pessoal de Saúde , Atenção à Saúde/organização & administração , Aconselhamento Genético/organização & administração , Adulto , Humanos , Recursos HumanosAssuntos
Testes Genéticos , Adulto , Quinase do Ponto de Checagem 2/genética , Feminino , Aconselhamento Genético/métodos , Aconselhamento Genético/normas , Predisposição Genética para Doença/genética , Testes Genéticos/normas , Variação Genética/genética , Humanos , Neoplasias/genética , Reprodutibilidade dos Testes , Medição de Risco/métodosRESUMO
CancerGene Connect (CGC) is a web-based program that combines the collection of family and medical history, cancer risk assessment, psychosocial assessment, report templates, a result tracking system, and a patient follow up system. The performance of CGC was assessed in several ways: pre-appointment completion data analyzed for demographic and health variables; a time study to assess overall time per case and to compare the data entry by the genetic counselor compared to the patient, and a measured quality assessment of the program via observation and interview of patients. Prior to their appointment, 52.3% of 2,414 patients completed the online patient questionnaire section of CGC. There were significant differences in completion rates among racial and ethnic groups. County hospital patients were less likely to complete the questionnaire than insured patients (p < 0.0001); and likewise uninsured patients and patients with Medicare/Medicaid were less likely to complete the questionnaire than private patients (p < 0.0001). The average genetic counseling time per case was 82 min, with no significant differences whether the counselor or the patient completed CGC. CGC reduces genetic counselor time by approximately 14-46% compared to average time per case using traditional risk assessment and documentation methods previously reported. All surveyed users felt the questionnaire was easy to understand. CGC is an effective tool that streamlines workflow, and provides a standardized data collection tool that can be used to evaluate and improve the genetic counseling process.
Assuntos
Aconselhamento Genético/métodos , Testes Genéticos/métodos , Neoplasias/diagnóstico , Neoplasias/genética , Idoso , Feminino , Humanos , Internet , Masculino , Pessoa de Meia-Idade , Relações Profissional-Paciente , Projetos de Pesquisa , Medição de Risco , Inquéritos e Questionários , Estados UnidosRESUMO
PURPOSE: Germline genetic testing (GT) is recommended for men with prostate cancer (PC), but testing through traditional models is limited. The ProGen study examined a novel model aimed at providing access to GT while promoting education and informed consent. METHODS: Men with potentially lethal PC (metastatic, localized with a Gleason score of ≥8, persistent prostate-specific antigen after local therapy), diagnosis age ≤55 years, previous malignancy, and family history suggestive of a pathogenic variant (PV) and/or at oncologist's discretion were randomly assigned 3:1 to video education (VE) or in-person genetic counseling (GC). Participants had 67 genes analyzed (Ambry), with results disclosed via telephone by a genetic counselor. Outcomes included GT consent, GT completion, PV prevalence, and survey measures of satisfaction, psychological impact, genetics knowledge, and family communication. Two-sided Fisher's exact tests were used for between-arm comparisons. RESULTS: Over a 2-year period, 662 participants at three sites were randomly assigned and pretest VE (n = 498) or GC (n = 164) was completed by 604 participants (VE, 93.1%; GC, 88.8%), of whom 596 participants (VE, 98.9%; GC, 97.9%) consented to GT and 591 participants completed GT (VE, 99.3%; GC, 98.6%). These differences were not statistically significant although subtle differences in satisfaction and psychological impact were. Notably, 84 PVs were identified in 78 participants (13.2%), with BRCA1/2 PV comprising 32% of participants with a positive result (BRCA2 n = 21, BRCA1 n = 4). CONCLUSION: Both VE and traditional GC yielded high GT uptake without significant differences in outcome measures of completion, GT uptake, genetics knowledge, and family communication. The increased demand for GT with limited genetics resources supports consideration of pretest VE for patients with PC.
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Aconselhamento Genético , Neoplasias da Próstata , Humanos , Masculino , Pessoa de Meia-Idade , Proteína BRCA1/genética , Proteína BRCA2/genética , Estrogênios Conjugados (USP) , Aconselhamento Genético/métodos , Aconselhamento Genético/psicologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapiaRESUMO
The clathrin-associated protein, Huntingtin Interacting Protein 1 (HIP1), is overexpressed in multiple human epithelial tumors. Here, we report that HIP1 is a novel oncoprotein that transforms cells. HIP1-transformed cells, in contrast to RasV12-transformed cells, have dysregulation of multiple receptors involved in clathrin trafficking. Examples include upregulation of the epidermal growth factor receptor (EGFR) and the transferrin receptor. Furthermore, accumulation of transferrin and EGF in the HIP1-transformed cells was increased, and breast tumors that had EGFR expressed also had HIP1 upregulated. Thus, HIP1 overexpression promotes tumor formation and is associated with a general alteration in receptor trafficking. HIP1 is the first endocytic protein to be directly implicated in tumor formation.
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Proteínas de Transporte/genética , Proteínas de Ligação a DNA , Animais , Apoptose , Western Blotting , Ciclo Celular , Divisão Celular , Linhagem Celular Transformada , Transformação Celular Neoplásica , DNA Complementar/metabolismo , Endocitose , Receptores ErbB/metabolismo , Citometria de Fluxo , Humanos , Camundongos , Camundongos Nus , Microscopia Confocal , Modelos Biológicos , Células NIH 3T3 , Fosforilação , Regiões Promotoras Genéticas , Transporte Proteico , Fatores de Tempo , Transferrina/metabolismoRESUMO
Mutations in the BRCA1 tumor suppressor gene, such as 5382insC (BRCA1insC), give carriers an increased risk for breast, ovarian, prostate, and pancreatic cancers. We have previously reported that, in mice, Brca1 deficiency in the hematopoietic system leads to pancytopenia and, as a result, early lethality. We explored the cellular consequences of Brca1-null and BRCA1insC alleles in combination with Trp53 deficiency in the murine hematopoietic system. We found that Brca1 and Trp53 codeficiency led to a highly penetrant erythroproliferative disorder that is characterized by hepatosplenomegaly and by expanded megakaryocyte erythroid progenitor (MEP) and immature erythroid blast populations. The expanded erythroid progenitor populations in both BM and spleen had the capacity to transmit the disease into secondary mouse recipients, suggesting that Brca1 and Trp53 codeficiency provides a murine model of hematopoietic neoplasia. This Brca1/Trp53 model replicated Poly (ADP-ribose) polymerase (PARP) inhibitor olaparib sensitivity seen in existing Brca1/Trp53 breast cancer models and had the benefits of monitoring disease progression and drug responses via peripheral blood analyses without sacrificing experimental animals. In addition, this erythroid neoplasia developed much faster than murine breast cancer, allowing for increased efficiency of future preclinical studies.
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Antineoplásicos , Neoplasias , Animais , Camundongos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Antineoplásicos/farmacologia , Poli(ADP-Ribose) Polimerases/genética , MutaçãoRESUMO
Huntingtin interacting protein 1 related (Hip1r) is an F-actin- and clathrin-binding protein involved in vesicular trafficking. In this study, we demonstrate that Hip1r is abundantly expressed in the gastric parietal cell, predominantly localizing with F-actin to canalicular membranes. Hip1r may provide a critical function in vivo, as demonstrated by extensive changes to parietal cells and the gastric epithelium in Hip1r-deficient mice. Electron microscopy revealed abnormal apical canalicular membranes and loss of tubulovesicles in mutant parietal cells, suggesting that Hip1r is necessary for the normal trafficking of these secretory membranes. Accordingly, acid secretory dynamics were altered in mutant parietal cells, with enhanced activation and acid trapping, as measured in isolated gastric glands. At the whole-organ level, gastric acidity was reduced in Hip1r-deficient mice, and the gastric mucosa was grossly transformed, with fewer parietal cells due to enhanced apoptotic cell death and glandular hypertrophy associated with cellular transformation. Hip1r-deficient mice had increased expression of the gastric growth factor gastrin, and mice mutant for both gastrin and Hip1r exhibited normalization of both proliferation and gland height. Taken together, these studies demonstrate that Hip1r plays a significant role in gastric physiology, mucosal architecture, and secretory membrane dynamics in parietal cells.
Assuntos
Proteínas de Ligação a DNA/fisiologia , Células Parietais Gástricas/fisiologia , Vesículas Secretórias/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Celulas Principais Gástricas/metabolismo , Celulas Principais Gástricas/patologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Ácido Gástrico/metabolismo , Determinação da Acidez Gástrica , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Gastrinas/sangue , Gastrinas/genética , Expressão Gênica/efeitos dos fármacos , ATPase Trocadora de Hidrogênio-Potássio/genética , ATPase Trocadora de Hidrogênio-Potássio/metabolismo , Histamina/farmacologia , Fator Intrínseco/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Proteínas dos Microfilamentos , Microscopia Eletrônica , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Células Parietais Gástricas/efeitos dos fármacos , Coelhos , Ranitidina/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Vesículas Secretórias/ultraestruturaRESUMO
Internalization of activated receptors regulates signaling, and endocytic adaptor proteins are well-characterized in clathrin-mediated uptake. One of these adaptor proteins, huntingtin interacting protein 1 (HIP1), induces cellular transformation and is overexpressed in some prostate cancers. We have discovered that HIP1 associates with the androgen receptor through a central coiled coil domain and is recruited to DNA response elements upon androgen stimulation. HIP1 is a novel androgen receptor regulator, significantly repressing transcription when knocked down using a silencing RNA approach and activating transcription when overexpressed. We have also identified a functional nuclear localization signal at the COOH terminus of HIP1, which contributes to the nuclear translocation of the protein. In conclusion, we have discovered that HIP1 is a nucleocytoplasmic protein capable of associating with membranes and DNA response elements and regulating transcription.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Receptores Androgênicos/metabolismo , Sequência de Aminoácidos , Animais , Células COS , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Chlorocebus aethiops , Proteínas de Ligação a DNA/genética , Endocitose , Metabolismo dos Lipídeos , Masculino , Dados de Sequência Molecular , Mutação , Sinais de Localização Nuclear/genética , Sinais de Localização Nuclear/metabolismo , Neoplasias da Próstata , Transporte Proteico , Interferência de RNA , Elementos de Resposta , Transcrição GênicaRESUMO
PURPOSE: Hereditary cancer genetic testing can inform personalized medical management for individuals at increased cancer risk. However, many variants in cancer predisposition genes are individually rare, and traditional tools may be insufficient to evaluate pathogenicity. This analysis presents data on variant classification and reclassification over a 20-year period. PATIENTS AND METHODS: This is a retrospective analysis of > 1.9 million individuals who received hereditary cancer genetic testing from a single clinical laboratory (March 1997 to December 2017). Variant classification included review of evidence from traditional tools (eg, population frequency databases, literature) and laboratory-developed tools (eg, novel statistical methods, in-house RNA analysis) by a multidisciplinary expert committee. Variants may have been reclassified more than once and with more than one line of evidence. RESULTS: In this time period, 62,842 unique variants were observed across 25 cancer predisposition genes, and 2,976 variants were reclassified. Overall, 82.1% of reclassification events were downgrades (eg, variant of uncertain significance [VUS] to benign), and 17.9% were upgrades (eg, VUS to pathogenic). Among reclassified variants, 82.8% were initially classified as VUS, and 47.5% were identified in ≤ 20 individuals (allele frequency ≤ 0.001%). Laboratory-developed tools were used in 72.3% of variant reclassification events, which affected > 600,000 individuals. More than 1.3 million patients were identified as carrying a variant that was reclassified within this 20-year time period. CONCLUSION: The variant classification program used by the laboratory evaluated here enabled the reclassification of variants that were individually rare. Laboratory-developed tools were a key component of this program and were used in the majority of reclassifications. This demonstrates the importance of using robust and novel tools to reclassify rare variants to appropriately inform personalized medical management.
RESUMO
Huntingtin interacting protein 1 (HIP1) is a multidomain oncoprotein whose expression correlates with increased epidermal growth factor receptor (EGFR) levels in certain tumors. For example, HIP1-transformed fibroblasts and HIP1-positive breast cancers have elevated EGFR protein levels. The combined association of HIP1 with huntingtin, the protein that is mutated in Huntington's disease, and the known overexpression of EGFR in glial brain tumors prompted us to explore HIP1 expression in a group of patients with different types of brain cancer. We report here that HIP1 is overexpressed with high frequency in brain cancers and that this overexpression correlates with EGFR and platelet-derived growth factor beta receptor expression. Furthermore, serum samples from patients with brain cancer contained anti-HIP1 antibodies more frequently than age-matched brain cancer-free controls. Finally, we report that HIP1 physically associates with EGFR and that this association is independent of the lipid, clathrin, and actin interacting domains of HIP1. These findings suggest that HIP1 may up-regulate or maintain EGFR overexpression in primary brain tumors by directly interacting with the receptor. This novel HIP1-EGFR interaction may work with or independent of HIP1 modulation of EGFR degradation via clathrin-mediated membrane trafficking pathways. Further investigation of HIP1 function in brain cancer biology and validation of its use as a prognostic or predictive brain tumor marker are now warranted.
Assuntos
Neoplasias Encefálicas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Receptores ErbB/metabolismo , Actinas/metabolismo , Anticorpos Antineoplásicos/sangue , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/metabolismo , Encéfalo/metabolismo , Neoplasias Encefálicas/imunologia , Clatrina/metabolismo , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/imunologia , Receptores ErbB/biossíntese , Humanos , Imunoprecipitação , Metabolismo dos Lipídeos , Ligação ProteicaRESUMO
Huntingtin interacting protein 1 (HIP1) is an inositol lipid, clathrin, and actin binding protein that is overexpressed in a variety of epithelial malignancies. Here, we report for the first time that HIP1 is elevated in non-Hodgkin's and Hodgkin's lymphomas and that patients with lymphoid malignancies frequently had anti-HIP1 antibodies in their serum. Moreover, p53-deficient mice with B-cell lymphomas were 13 times more likely to have anti-HIP1 antibodies in their serum than control mice. Furthermore, transgenic overexpression of HIP1 was associated with the development of lymphoid neoplasms. The HIP1 protein was induced by activation of the nuclear factor-kappaB pathway, which is frequently activated in lymphoid malignancies. These data identify HIP1 as a new marker of lymphoid malignancies that contributes to the transformation of lymphoid cells in vivo.
Assuntos
Proteínas de Ligação a DNA/biossíntese , Linfoma/metabolismo , Animais , Anticorpos Antineoplásicos/sangue , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Modelos Animais de Doenças , Doença de Hodgkin/genética , Doença de Hodgkin/metabolismo , Humanos , Linfoma/genética , Linfoma/patologia , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NF-kappa B/metabolismo , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genéticaRESUMO
In 2016, the UT Southwestern Medical Center's Cancer Genetics Program was awarded a grant (PP160103) by the Cancer Prevention and Research Institute of Texas (CPRIT) to increase awareness of hereditary cancer syndromes, particularly Lynch syndrome (LS), and implement a population-based genetic screening program to identify those at high genetic risk for cancer.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Detecção Precoce de Câncer , Família , Testes Genéticos , Programas de Rastreamento , Anamnese , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias do Endométrio/etiologia , Neoplasias do Endométrio/genética , Feminino , Humanos , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/genética , Fatores de Risco , TexasRESUMO
Both BRCA1 and CREBBP are tumor suppressor genes that are important for hematopoiesis. We have previously shown that mouse Brca1 is essential for hematopoietic stem cell (HSC) viability. In contrast to Brca1 deficiency, which results in pancytopenia, we report here that Crebbp deficiency results in myeloproliferation associated with an increase of splenic HSCs as well as a lethal systemic inflammatory disorder (LD50 = 86 days). To investigate the interaction of these two proteins in hematopoiesis, we generated double Crebbp/Brca1 knockout mice (DKOs). To our surprise, DKOs had accelerated bone marrow failure compared with Brca1-deficient mice and this was associated with an even shorter lifespan (LD50 = 88.5 versus 33 days). Furthermore, Crebbp or Brca1 heterozygosity influenced the hematopoietic phenotype associated with complete deficiency of Brca1 or Crebbp, respectively. We also observed lower BRCA1 protein levels in hematopoietic tissues when CREBBP is absent. Collectively, these data suggest Crebbp and Brca1 functionally interact to maintain normal hematopoiesis.
RESUMO
BACKGROUND: There are no national guidelines for the management of patients with a family history consistent with Lynch syndrome (LS) but a negative genetic test. To determine current management practices, genetic counselors' (GCs) recommendations were assessed. METHODS: A survey of GCs using five hypothetical pedigrees was posted to National Society of Genetic Counselors (NSGC) discussion forums. Descriptive statistics were used. RESULTS: One-hundred and fifteen surveys were completed. A pedigree with a first-degree relative (FDR) with early-onset colorectal cancer (CRC) and a family history of CRC and endometrial cancer (EC) prompted 83% (n = 95) of respondents to recommend early and frequent colonoscopies, based on family history. When the CRCs and ECs occurred in family members removed from the proband, 96% (n = 110) of GCs said they would screen based on family history. However, only 52% (n = 60) suggested CRC screening should begin earlier and occur more often, and 43% (n = 50) suggested CRC screening should follow standard age and frequency guidelines. CONCLUSION: Concordance of opinion among GCs for the management of patients with negative genetic test results exists when FDRs are affected. However, when affected relatives are more distant, GCs disagreed on screening recommendations. These data suggest a need for guidelines for patients with a family history of cancer and a negative genetic test.
Assuntos
Neoplasias do Colo/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias do Endométrio/genética , Família , Aconselhamento Genético , Linhagem , Adulto , Feminino , Humanos , MasculinoRESUMO
Inflammatory bowel disease (IBD) affects 1.5-3.0 million people in the United States. IBD is genetically determined and many common risk alleles have been identified. Yet, a large proportion of genetic predisposition remains unexplained. In this study, we report the identification of an ultr arare missense variant (NM_006998.3:c.230G > A;p.Arg77His) in the SCGN gene causing Mendelian early-onset ulcerative colitis. SCGN encodes a calcium sensor that is exclusively expressed in neuroendocrine lineages, including enteroendocrine cells and gut neurons. SCGN interacts with the SNARE complex, which is required for vesicle fusion with the plasma membrane. We show that the SCGN mutation identified impacted the localization of the SNARE complex partner, SNAP25, leading to impaired hormone release. Finally, we show that mouse models of Scgn deficiency recapitulate impaired hormone release and susceptibility to DSS-induced colitis. Altogether, these studies demonstrate that functional deficiency in SCGN can result in intestinal inflammation and implicates the neuroendocrine cellular compartment in IBD.
Assuntos
Colite Ulcerativa/genética , Predisposição Genética para Doença , Secretagoginas/deficiência , Animais , Membrana Celular/metabolismo , Vesículas Citoplasmáticas/metabolismo , Modelos Animais de Doenças , Humanos , Fusão de Membrana , Camundongos , Mutação de Sentido Incorreto , Transporte Proteico , Proteínas SNARE/metabolismo , Secretagoginas/genética , Proteína 25 Associada a Sinaptossoma/metabolismoRESUMO
Deficiency of huntingtin-interacting protein 1 (Hip1) results in degenerative phenotypes. Here we generated a Hip1 deficiency allele where a floxed transcriptional stop cassette and a human HIP1 cDNA were knocked into intron 1 of the mouse Hip1 locus. CMV-Cre-mediated germ line excision of the stop cassette resulted in expression of HIP1 and rescue of the Hip1 knockout phenotype. Mx1-Cre-mediated excision led to HIP1 expression in spleen, kidney and liver, and also rescued the phenotype. In contrast, hGFAP-Cre-mediated, brain-specific HIP1 expression did not rescue the phenotype. Metabolomics and microarrays of several Hip1 knockout tissues identified low phosphocholine (PC) levels and low glycerophosphodiester phosphodiesterase domain containing 3 (Gdpd3) gene expression. Since Gdpd3 has lysophospholipase D activity that results in the formation of choline, a precursor of PC, Gdpd3 downregulation could lead to the low PC levels. To test whether Gdpd3 contributes to the Hip1 deficiency phenotype, we generated Gdpd3 knockout mice. Double knockout of Gdpd3 and Hip1 worsened the Hip1 phenotype. This suggests that Gdpd3 compensates for Hip1 loss. More-detailed knowledge of how Hip1 deficiency leads to low PC will improve our understanding of HIP1 in choline metabolism in normal and disease states.