RESUMEN
Gorlin syndrome (MIM 109,400), a cancer predisposition syndrome related to a constitutional pathogenic variation (PV) of a gene in the Sonic Hedgehog pathway (PTCH1 or SUFU), is associated with a broad spectrum of benign and malignant tumors. Basal cell carcinomas (BCC), odontogenic keratocysts and medulloblastomas are the main tumor types encountered, but meningiomas, ovarian or cardiac fibromas and sarcomas have also been described. The clinical features and tumor risks are different depending on the causative gene. Due to the rarity of this condition, there is little data on phenotype-genotype correlations. This report summarizes genotype-based recommendations for screening patients with PTCH1 and SUFU-related Gorlin syndrome, discussed during a workshop of the Host Genome Working Group of the European branch of the International Society of Pediatric Oncology (SIOPE HGWG) held in January 2020. In order to allow early detection of BCC, dermatologic examination should start at age 10 in PTCH1, and at age 20 in SUFU PV carriers. Odontogenic keratocyst screening, based on odontologic examination, should begin at age 2 with annual orthopantogram beginning around age 8 for PTCH1 PV carriers only. For medulloblastomas, repeated brain MRI from birth to 5 years should be proposed for SUFU PV carriers only. Brain MRI for meningiomas and pelvic ultrasound for ovarian fibromas should be offered to both PTCH1 and SUFU PV carriers. Follow-up of patients treated with radiotherapy should be prolonged and thorough because of the risk of secondary malignancies. Prospective evaluation of evidence of the effectiveness of these surveillance recommendations is required.
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Síndrome del Nevo Basocelular , Neoplasias Cerebelosas , Neoplasias Cutáneas , Síndrome del Nevo Basocelular/diagnóstico , Síndrome del Nevo Basocelular/genética , Neoplasias Cerebelosas/diagnóstico , Neoplasias Cerebelosas/genética , Niño , Preescolar , Proteínas Hedgehog/genética , Humanos , Receptor Patched-1/genética , Proteínas Represoras/genética , Adulto JovenRESUMEN
The rhabdoid tumor (RT) predisposition syndromes 1 and 2 (RTPS1 and 2) are rare genetic conditions rendering young children vulnerable to an increased risk of RT, malignant neoplasms affecting the kidney, miscellaneous soft-part tissues, the liver and the central nervous system (Atypical Teratoid Rhabdoid Tumors, ATRT). Both, RTPS1&2 are due to pathogenic variants (PV) in genes encoding constituents of the BAF chromatin remodeling complex, i.e. SMARCB1 (RTPS1) and SMARCA4 (RTPS2). In contrast to other genetic disorders related to PVs in SMARCB1 and SMARCA4 such as Coffin-Siris Syndrome, RTPS1&2 are characterized by a predominance of truncating PVs, terminating transcription thus explaining a specific cancer risk. The penetrance of RTPS1 early in life is high and associated with a poor survival. However, few unaffected carriers may be encountered. Beyond RT, the tumor spectrum may be larger than initially suspected, and cancer surveillance offered to unaffected carriers (siblings or parents) and long-term survivors of RT is still a matter of discussion. RTPS2 exposes female carriers to an ill-defined risk of small cell carcinoma of the ovaries, hypercalcemic type (SCCOHT), which may appear in prepubertal females. RT surveillance protocols for these rare families have not been established. To address unresolved issues in the care of individuals with RTPS and to propose appropriate surveillance guidelines in childhood, the SIOPe Host Genome working group invited pediatric oncologists and geneticists to contribute to an expert meeting. The current manuscript summarizes conclusions of the panel discussion, including consented statements as well as non-evidence-based proposals for validation in the future.
Asunto(s)
Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Neoplasias Renales , Tumor Rabdoide , Neoplasias Encefálicas/genética , Preescolar , ADN Helicasas/genética , Femenino , Pruebas Genéticas , Humanos , Neoplasias Renales/genética , Proteínas Nucleares , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/genética , Proteína SMARCB1/genética , Factores de Transcripción/genéticaRESUMEN
The Li-Fraumeni syndrome (LFS, online Mendelian inheritance in man, OMIM #151623) is considered to be one of the currently known most aggressive cancer predisposition syndromes. The heterogeneous spectrum of tumors is dominated by bone and soft tissue sarcomas, various brain tumors, premenopausal breast cancer and adrenocortical carcinoma (ACC). Even in childhood the cancer risk is very strongly increased and it is not uncommon for people with LFS to develop synchronous and metachronous tumors. Typical histopathological findings and molecular genetic signatures can help towards the diagnosis. Inheritance is autosomal dominant and the penetrance appears to be more variable than previously thought. The prevalence of LFS is approximately 1:5000 with a high interregional variance. The LFS is caused by germline mutations in the TP53 gene coding for the protein p53, an essential cellular transcription factor that initiates antitumor responses to cellular stress, such as DNA damage. In people with LFS, due to the loss of functional p53, the protective mechanism of the cells is weakened resulting in a significantly increased cancer risk. In order to improve the survival of people with LFS, structured tumor early recognition and surveillance strategies are recommended; however, national and international longitudinal observational studies are needed to evaluate the cost-effort-benefit balance. For this reason, the authors have established the LFS cancer predisposition registry in which all patients with LFS and other syndromes predisposing to cancer can be registered. Detailed information can be found at www.cancer-predisposition.org .
Asunto(s)
Predisposición Genética a la Enfermedad , Síndrome de Li-Fraumeni , Genes p53/genética , Humanos , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/mortalidad , Síndrome de Li-Fraumeni/patologíaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Dexametasona/administración & dosificación , Eliminación de Gen , Factor de Transcripción Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Asparaginasa/administración & dosificación , Niño , Preescolar , Ciclofosfamida/administración & dosificación , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Humanos , Mercaptopurina/administración & dosificación , Metotrexato/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prednisona/administración & dosificación , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
Nasopharyngeal carcinoma (NPC) is a rare malignant tumor arising from epithelial cells of the nasopharynx. Its incidence is highest in Southeast Asia. Age distribution of NPC is bimodal, with one peak in young adolescents and another in patients 55-59 years of age. EBV appears to be the primary etiologic agent in the pathogenesis, environmental factors such as nitrosamines and genetic factors are contributory. NPC is most commonly diagnosed in locally advanced stages, with lymph node metastases occurring in up to 90% of patients. About 5-10% of patients present with distant metastases. Diagnosis of NPC is made histologically, supported by an abnormal anti-EBV-VCA IgA titer and elevated plasma EBV-DNA load. Superior results in children and adolescents with advanced locoregional NPC, with overall and event-free survival rates>90%, have been achieved by neoadjuvant chemotherapy with 5-fluoruracil and cisplatin, followed by synchronous radiochemotherapy and subsequent maintenance therapy with interferon-ß as demonstrated by the 2 prospective studies GPOH-NPC-91 and -2003. Response to therapy can be assessed by PET-imaging and in patients with complete remission after neoadjuvant chemotherapy, the radiation dose to the primary tumor can be safely reduced from 59.4 to 54.4 Gy. Since the majority of long term sequalae such as xerostomia, skin and tissue fibrosis are caused by high radiation dosages, radiotherapy modalities such as intensity-modulated radiotherapy should be used to efficiently spare non-tumorous tissue. For patients with metastatic disease and relapse, survival chances are low. New treatment strategies, such as the application of EBV-specific T-lymphocytes should be considered for these patients.
Asunto(s)
Neoplasias Nasofaríngeas/diagnóstico , Adolescente , Biomarcadores de Tumor/análisis , Niño , Terapia Combinada , ADN Viral/análisis , Infecciones por Virus de Epstein-Barr/diagnóstico , Infecciones por Virus de Epstein-Barr/mortalidad , Infecciones por Virus de Epstein-Barr/patología , Infecciones por Virus de Epstein-Barr/terapia , Humanos , Ganglios Linfáticos/patología , Metástasis Linfática/patología , Imagen por Resonancia Magnética , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/terapia , Nasofaringe/patología , Estadificación de Neoplasias , Tasa de Supervivencia , Adulto JovenRESUMEN
INTRODUCTION: The etiology of acute lymphoblastic leukemia remains undisclosed in the majority of cases. A number of rare syndromic conditions are known to predispose to different forms of childhood cancer including ALL. The present study characterized the spectrum and clinical impact of preexisting diseases in a cohort of ALL patients from Germany, Austria and Switzerland with a focus on genetic diseases predisposing to cancer development. METHODS: Retrospective database and study chart review included all patients from Germany, Austria and Switzerland (n = 4939) enrolled into multicenter clinical trial AIEOP-BFM ALL 2000 between July 1999 and June 2009. Patients enrolled into study AIEOP-BFM ALL 2009 - which was initiated subsequent to AIEP-BFM ALL 2000 - who were reported with a cancer prone syndrome or chromosomal abnormality were additionally included in this study to increase conclusiveness of observations. RESULTS: A total of 233 patients with at least one reported condition could be identified. The following conditions were reported in more than one patient: Gilbert's disease (n = 13), neurofibromatosis type I (n = 8), ataxia telangiectasia (n = 8), thalassemia (n = 7), Nijmegen Breakage syndrome (n = 6), cystic fibrosis (n = 4), glucose-6-phosphate dehydrogenase deficiency (n = 4), Noonan syndrome (n = 2), Klinefelter syndrome (n = 2), alpha-1-antitrypsin deficiency (n = 2), primary ciliary dyskinesia (n = 2). Especially those syndromes with a known cancer predisposition (NF type I, Ataxia telangiectasia, Nijmegen Breakage syndrome etc.) were associated with certain general and ALL-related characteristics, high therapy-related toxicity and reduced survival. CONCLUSION: The spectrum of underlying diseases within ALL patients is dispersed. A small number of ALL patients are reported with cancer predisposition syndromes at initial diagnosis which are associated with high rates of therapy-related toxicity and a markedly reduced chance of survival. The true prevalence of these conditions within the ALL population remains unknown due to inapparent clinical presentation. A targeted clinical and/or genetic examination for certain diagnoses like NF type I, Ataxia telangiectasia or Nijmegen Breakage syndrome could identify patients who benefit from adjustment of antileukemic therapy or intensification of supportive care.
Asunto(s)
Susceptibilidad a Enfermedades , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Adolescente , Factores de Edad , Austria/epidemiología , Niño , Preescolar , Ensayos Clínicos como Asunto , Femenino , Predisposición Genética a la Enfermedad , Alemania/epidemiología , Humanos , Lactante , Recién Nacido , Masculino , Estudios Multicéntricos como Asunto , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Prevalencia , Estudios Retrospectivos , Suiza/epidemiologíaRESUMEN
Fanconi anemia (FA) is a genomic instability syndrome associated with bone marrow failure, myelodysplastic syndrome (MDS), and/or acute myeloid leukemia (AML) requiring hematopoietic stem cell transplantation (HSCT) to restore normal hematopoiesis. Although low-intensity fludarabine-based preparative regimens without radiation confer excellent outcomes in FA HSCTs with HLA-matched sibling donors, outcomes for FA patients with alternative donors are less encouraging, albeit improving. We present our experience with 17 FA patients who completed mismatched related or unrelated donor HSCT using a non-radiation fludarabine-based preparative regimen at Charité University Medicine Berlin. All patients engrafted; however, one patient had unstable chimerism in the setting of multi-viral infections that necessitated a stem cell boost to revert to full donor chimerism. Forty-seven percent of patients developed grade I acute graft-verus-host disease (aGVHD). No grade II-IV aGVHD or chronic graft-versus-host disease of any severity occurred. At a median follow-up of 30 months, 88 % of patients are alive with normal hematopoiesis. Two patients died of infections 4 months post-transplantation. These results demonstrate that short-term outcomes for FA patients with mismatched and unrelated donor HSCTs can be excellent using chemotherapy only conditioning. Viral reactivation, however, was a major treatment-related complication.
Asunto(s)
Antineoplásicos/administración & dosificación , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodos , Donante no Emparentado , Adolescente , Niño , Preescolar , Femenino , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/tendencias , Humanos , Masculino , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Somatic mutations affecting components of the Ras-MAPK pathway are a common feature of cancer, whereas germline Ras pathway mutations cause developmental disorders including Noonan, Costello, and cardio-facio-cutaneous syndromes. These 'RASopathies' also represent cancer-prone syndromes, but the quantitative cancer risks remain unknown. METHODS: We investigated the occurrence of childhood cancer including benign and malignant tumours of the central nervous system in a group of 735 individuals with germline mutations in Ras signalling pathway genes by matching their information with the German Childhood Cancer Registry. RESULTS: We observed 12 cases of cancer in the entire RASopathy cohort vs 1.12 expected (based on German population-based incidence rates). This corresponds to a 10.5-fold increased risk of all childhood cancers combined (standardised incidence ratio (SIR)=10.5, 95% confidence interval=5.4-18.3). The specific cancers included juvenile myelomonocytic leukaemia=4; brain tumour=3; acute lymphoblastic leukaemia=2; rhabdomyosarcoma=2; and neuroblastoma=1. The childhood cancer SIR in Noonan syndrome patients was 8.1, whereas that for Costello syndrome patients was 42.4. CONCLUSIONS: These data comprise the first quantitative evidence documenting that the germline mutations in Ras signalling pathway genes are associated with increased risks of both childhood leukaemia and solid tumours.
Asunto(s)
Síndrome de Costello/genética , Displasia Ectodérmica/genética , Insuficiencia de Crecimiento/genética , Cardiopatías Congénitas/genética , Neoplasias/epidemiología , Síndrome de Noonan/genética , Proteínas ras/genética , Adolescente , Niño , Preescolar , Síndrome de Costello/patología , Displasia Ectodérmica/patología , Facies , Insuficiencia de Crecimiento/patología , Femenino , Mutación de Línea Germinal , Alemania/epidemiología , Cardiopatías Congénitas/patología , Humanos , Lactante , Masculino , Neoplasias/etiología , Neoplasias/patología , Síndrome de Noonan/patología , Sistema de Registros , Factores de Riesgo , Transducción de SeñalRESUMEN
Lynch syndrome (LS) is an autosomal dominant disorder caused by a defect in one of the DNA mismatch repair genes: MLH1, MSH2, MSH6 and PMS2. In the last 15 years, an increasing number of patients have been described with biallelic mismatch repair gene mutations causing a syndrome referred to as 'constitutional mismatch repair-deficiency' (CMMR-D). The spectrum of cancers observed in this syndrome differs from that found in LS, as about half develop brain tumours, around half develop digestive tract cancers and a third develop haematological malignancies. Brain tumours and haematological malignancies are mainly diagnosed in the first decade of life, and colorectal cancer (CRC) and small bowel cancer in the second and third decades of life. Surveillance for CRC in patients with LS is very effective. Therefore, an important question is whether surveillance for the most common CMMR-D-associated cancers will also be effective. Recently, a new European consortium was established with the aim of improving care for patients with CMMR-D. At a workshop of this group held in Paris in June 2013, one of the issues addressed was the development of surveillance guidelines. In 1968, criteria were proposed by WHO that should be met prior to the implementation of screening programmes. These criteria were used to assess surveillance in CMMR-D. The evaluation showed that surveillance for CRC is the only part of the programme that largely complies with the WHO criteria. The values of all other suggested screening protocols are unknown. In particular, it is questionable whether surveillance for haematological malignancies improves the already favourable outcome for patients with these tumours. Based on the available knowledge and the discussions at the workshop, the European consortium proposed a surveillance protocol. Prospective collection of all results of the surveillance is needed to evaluate the effectiveness of the programme.
Asunto(s)
Neoplasias Encefálicas/diagnóstico , Trastornos por Deficiencias en la Reparación del ADN/genética , Neoplasias del Sistema Digestivo/diagnóstico , Neoplasias/diagnóstico , Neoplasias Encefálicas/etiología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/tratamiento farmacológico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Trastornos por Deficiencias en la Reparación del ADN/complicaciones , Humanos , Leucemia/diagnóstico , Mutación , Neoplasias/etiología , Vigilancia de la PoblaciónRESUMEN
Recently, germline mutations of DICER1 have been identified in patients with rare neoplasms suggesting the existence of a newly discovered cancer prone syndrome. Initially, DICER1 mutations were identified in patients with familial pleuropulmonary blastoma. Subsequently, additional manifestations of the syndrome have been identified including cystic nephroma, medulloepithelioma, Sertoli-Leydig cell tumor and others. The DICER1 gene encodes an enzyme that is involved in the biogenesis of microRNAs. The entire tumor spectrum and the respective tumor risks are unknown. We are in the process of launching a natural history study aimed at identifying more information on this new cancer syndrome.
Asunto(s)
ARN Helicasas DEAD-box/genética , Neoplasias Pulmonares/genética , Síndromes Neoplásicos Hereditarios/genética , Blastoma Pulmonar/genética , Ribonucleasa III/genética , Niño , Cromosomas Humanos Par 14 , Tamización de Portadores Genéticos , Mutación de Línea Germinal , Humanos , MicroARNs/genética , Sistema de RegistrosRESUMEN
Three genome-wide association studies of testicular cancer have uncovered predisposition alleles in or near KITLG, BAK1, SPRY4, TERT, ATF7IP and DMRT1. We investigated whether testicular cancer-risk alleles can be utilized in the clinical setting. We employed the receiver operating characteristic curves for genetic risk models to measure the discriminatory power of a risk variant-based risk model, and found that the newly discovered variants provided a discriminatory power of 69.2%. This suggested that about 69.2% of the time, a randomly selected patient with testicular cancer had a higher estimated risk than the risk for a randomly selected control subject. Using a multiplicative model, we estimated that white men in the top 1% of genetic risk as defined by eight risk variants had a relative risk that was 10.5-fold greater than that for the general white male population. This risk differential does not appear to be clinically useful, given the relative rarity and highly curable nature of testicular germ cell tumour (TGCT). In the authors' view, a stratified genetic risk assessment strategy might be useful, theoretically, for men who also have independent clinical risk factors for testicular cancer. Several established TGCT risk factors, such as cryptorchidism (RR=4.8) and male infertility (SIR=2.8) might prove useful in that context, but we currently do not know whether these testicular cancer-risk loci are associated with, or independent of, such clinical risk factors. More research is required before we can utilize testicular cancer-risk loci for clinically meaningful risk prediction.
Asunto(s)
Predisposición Genética a la Enfermedad , Neoplasias de Células Germinales y Embrionarias/epidemiología , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias Testiculares/epidemiología , Neoplasias Testiculares/genética , Mapeo Cromosómico , Criptorquidismo , Estudio de Asociación del Genoma Completo , Humanos , Infertilidad , Masculino , Neoplasias de Células Germinales y Embrionarias/patología , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Neoplasias Testiculares/patologíaRESUMEN
BACKGROUND: Biallelic germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 or PMS2 cause a recessive childhood cancer syndrome characterised by early-onset malignancies and signs reminiscent of neurofibromatosis type 1 (NF1). Alluding to the underlying genetic defect, we refer to this syndrome as constitutional mismatch repair-deficiency (CMMR-D) syndrome. The tumour spectrum of CMMR-D syndrome includes haematological neoplasias, brain tumours and Lynch syndrome-associated tumours. Other tumours, such as neuroblastoma, Wilm tumour, ovarian neuroectodermal tumour or infantile myofibromatosis, have so far been found only in individual cases. RESULTS: We analysed two consanguineous families that had members with suspected CMMR-D syndrome who developed rhabdomyosarcoma among other neoplasias. In the first family, we identified a pathogenic PMS2 mutation for which the affected patient was homozygous. In family 2, immunohistochemistry analysis showed isolated loss of PMS2 expression in all tumours in the affected patients, including rhabdomyosarcoma itself and the surrounding normal tissue. Together with the family history and microsatellite instability observed in one tumour this strongly suggests an underlying PMS2 alteration in family 2 also. CONCLUSION: Together, these two new cases show that rhabdomyosarcoma and possibly other embryonic tumours, such as neuroblastoma and Wilm tumour, belong to the tumour spectrum of CMMR-D syndrome. Given the clinical overlap of CMMR-D syndrome with NF1, we suggest careful examination of the family history in patients with embryonic tumours and signs of NF1 as well as analysis of the tumours for loss of one of the mismatch repair genes and microsatellite instability. Subsequent mutation analysis will lead to a definitive diagnosis of the underlying disorder.
Asunto(s)
Reparación de la Incompatibilidad de ADN/genética , Trastornos por Deficiencias en la Reparación del ADN/genética , Rabdomiosarcoma/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adenosina Trifosfatasas/genética , Adenosina Trifosfatasas/metabolismo , Niño , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Trastornos por Deficiencias en la Reparación del ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Humanos , Inmunohistoquímica , Masculino , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Mutación , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Linaje , Rabdomiosarcoma/metabolismo , Análisis de Secuencia de ADN , Síndrome , Adulto JovenRESUMEN
Heterozygous germline mutations in one of the mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 cause hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome, a dominantly inherited cancer susceptibility syndrome. Recent reports provide evidence for a novel recessively inherited cancer syndrome with constitutive MMR deficiency due to biallelic germline mutations in one of the MMR genes. MMR-deficiency (MMR-D) syndrome is characterized by childhood brain tumors, hematological and/or gastrointestinal malignancies, and signs of neurofibromatosis type 1 (NF1). We established an RNA-based mutation detection assay for the four MMR genes, since 1) a number of splicing defects may escape detection by the analysis of genomic DNA, and 2) DNA-based mutation detection in the PMS2 gene is severely hampered by the presence of multiple highly similar pseudogenes, including PMS2CL. Using this assay, which is based on direct cDNA sequencing of RT-PCR products, we investigated two families with children suspected to suffer from MMR-D syndrome. We identified a homozygous complex MSH6 splicing alteration in the index patients of the first family and a novel homozygous PMS2 mutation (c.182delA) in the index patient of the second family. Furthermore, we demonstrate, by the analysis of a PMS2/PMS2CL "hybrid" allele carrier, that RNA-based PMS2 testing effectively avoids the caveats of genomic DNA amplification approaches; i.e., pseudogene coamplification as well as allelic dropout, and will, thus, allow more sensitive mutation analysis in MMR deficiency and in HNPCC patients with PMS2 defects.
Asunto(s)
Adenosina Trifosfatasas/genética , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Seudogenes , Empalme del ARN/genética , Análisis de Secuencia de ARN , Alelos , Secuencia de Bases , Niño , Análisis Mutacional de ADN , Humanos , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Datos de Secuencia Molecular , ARN Mensajero/genéticaAsunto(s)
Adenosina Trifosfatasas/genética , Manchas Café con Leche/genética , Neoplasias Colorrectales/genética , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Neoplasias Encefálicas/etiología , Neoplasias Encefálicas/genética , Niño , Neoplasias Colorrectales/etiología , Salud de la Familia , Femenino , Homocigoto , Humanos , Linfoma de Células T/etiología , Linfoma de Células T/genética , Endonucleasa PMS2 de Reparación del Emparejamiento IncorrectoAsunto(s)
Anemia/genética , Factor de Transcripción GATA1/genética , Mutación de Línea Germinal , Síndromes Mielodisplásicos/genética , Trombocitopenia/genética , Anemia/complicaciones , Anemia/congénito , Anemia/terapia , Transfusión de Eritrocitos , Salud de la Familia , Humanos , Recién Nacido , Masculino , Síndromes Mielodisplásicos/complicaciones , Trombocitopenia/complicacionesRESUMEN
Astrocytomas are the most common brain tumors of childhood. However, knowledge of the molecular etiology of astrocytomas WHO grade I and II is limited. Germline mutations in the Ras-guanosine triphosphatase-activating protein, neurofibromin, in individuals with neurofibromatosis type I predispose to pilocytic astrocytomas. This association suggests that constitutive activation of the Ras signaling pathway plays a fundamental role in astrocytoma development. We screened 25 WHO I and II astrocytomas for mutations of PTPN11, NRAS, KRAS, and HRAS genes and identified the somatic G12A KRAS mutation in one pilocytic astrocytoma. These data suggest that Ras is rarely mutated in these tumors. Analyzed astrocytomas without mutations in Ras or neurofibromin may harbor mutations in other proteins of this pathway leading to hyperactive Ras signaling.
Asunto(s)
Astrocitoma/genética , Neoplasias Encefálicas/genética , Mutación/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Astrocitoma/patología , Neoplasias Encefálicas/patología , Exones/genética , Humanos , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Transducción de Señal/genéticaRESUMEN
Porphobilinogen-synthase (PBG-synthase) is an enzyme extensively used as a bioindicator of metals and other oxidizing agents. The objective of this study was to verify the effects of HgCl(2) (5mg/kg/day, s.c.), a metal that mainly affects the nervous and renal systems, on kidney, liver and brain from rats exposed during one of the phases considered critical for development. Mercury decreased PBG-synthase activity from liver, kidney and brain and altered corporal, renal and cerebral weights. The kidney was the most sensitive tissue. It accumulated a large amount of metal and PBG-synthase activity was decreased up to 50%. The second period seemed to be the most sensitive, because in this phase the rats presented alterations in body, brain and kidney weights, and there was also an expressive inhibition in hepatic and renal PBG-synthase activities. In general, large quantities of metal accumulated in the tissues are in agreement with the inhibition verified in these tissues.
Asunto(s)
Cloruro de Mercurio/farmacología , Mercurio/metabolismo , Porfobilinógeno Sintasa/metabolismo , Animales , Animales Recién Nacidos , Peso Corporal/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Juvenile myelomonocytic leukemia (JMML) is a malignant hematopoietic disorder whose proliferative component is a result of RAS pathway deregulation caused by somatic mutation in the RAS or PTPN11 oncogenes or in patients with underlying neurofibromatosis type 1 (NF-1), by loss of NF1 gene function. To search for potential collaborating genetic abnormalities, we used oligonucleotide arrays to analyse over 116 000 single-nucleotide polymorphisms across the genome in 16 JMML samples with normal karyotype. Evaluation of the SNP genotypes identified large regions of homozygosity on chromosome 17q, including the NF1 locus, in four of the five samples from patients with JMML and NF-1. The homozygous region was at least 55 million base pairs in each case. The genomic copy number was normal within the homozygous region, indicating uniparental disomy (UPD). In contrast, the array data provided no evidence for 17q UPD in any of the 11 JMML cases without NF-1. We used array-based comparative genomic hybridization to confirm 17q disomy, and microsatellite analysis was performed to verify homozygosity. Mutational analysis demonstrated that the inactivating NF1 lesion was present on both alleles in each case. In summary, our data indicate that a mitotic recombination event in a JMML-initiating cell led to 17q UPD with homozygous loss of normal NF1, provide confirmatory evidence that the NF1 gene is crucial for the increased incidence of JMML in NF-1 patients, and corroborate the concept that RAS pathway deregulation is central to JMML pathogenesis.