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1.
Clin Dermatol ; 38(4): 421-431, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32972601

RESUMO

Café au lait spots are common birthmarks seen sporadically and in association with several genetic syndromes. Dermatologists are often asked to evaluate these birthmarks both by other physicians and by parents. In some cases, it is challenging to know when and how to pursue further evaluation. Diagnostic challenges may come in the form of the appearance of the individual lesions, areas and patterns of cutaneous involvement, and associated features (or lack thereof). In this review, we aim to clarify when and how to evaluate the child with multiple or patterned café au lait spots and to explain some emerging concepts in our understanding of the genetics of these lesions.


Assuntos
Manchas Café com Leite/congênito , Manchas Café com Leite/diagnóstico , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/genética , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/genética , Pele/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Manchas Café com Leite/genética , Manchas Café com Leite/patologia , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Deleção de Genes , Estudos de Associação Genética , Mutação em Linhagem Germinativa , Humanos , Lactente , Recém-Nascido , Masculino , Neurofibromatose 1/patologia , Neurofibromina 1/genética , Dermatopatias Genéticas/patologia , Síndrome
2.
Clin Dermatol ; 38(4): 455-461, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32972603

RESUMO

RASopathies are a group of disorders characterized by mutations in the RAS-MAPK pathway. RAS-MAP signaling plays a critical role in cell differentiation, proliferation, and survival. Germline mutations can result in distinctive syndromes, including Noonan syndrome, Costello syndrome, and neurofibromatosis type 1. Mosaic RASopathies can present as localized cutaneous lesions like epidermal nevi and nevus sebaceous, or more extensive conditions such as encephalocraniocutaneous lipomatosis. We review the heterogenous presentation of RAS mutations, discuss new targeted therapies, and highlight areas of uncertainty, including carcinogenesis risk and appropriate screening.


Assuntos
Síndrome de Costello/genética , Oftalmopatias/genética , Mutação em Linhagem Germinativa , Lipomatose/genética , Sistema de Sinalização das MAP Quinases/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Síndromes Neurocutâneas/genética , Neurofibromatose 1/genética , Síndrome de Noonan/genética , Síndrome de Costello/diagnóstico , Síndrome de Costello/terapia , Oftalmopatias/diagnóstico por imagem , Oftalmopatias/terapia , Humanos , Lipomatose/diagnóstico por imagem , Lipomatose/terapia , Terapia de Alvo Molecular , Mutação , Síndromes Neurocutâneas/diagnóstico por imagem , Síndromes Neurocutâneas/terapia , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/terapia , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/terapia , Risco
3.
Tokai J Exp Clin Med ; 45(3): 148-151, 2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-32901905

RESUMO

PURPOSE: Pheochromocytoma (PCC) and paraganglioma (PGL) associated with the succinate dehydrogenase (SDH) germline mutations are characterized by negative results of immunohistochemistry tests for SDH subunit B (SDHB). Genetic testing for the SDH complex (SDHA, SDHB, SDHC, SDHD, and SDHAF2) is indicated only in patients with those diseases in whom immunohistochemistry tests for SDHB as a surrogate marker to detect the SDH complex mutation yield negative results. Two novel SDHB germline mutations, L157X and P236S, in PGL were previously reported. We therefore examined immunohistochemistry testing for SDHB in the PGLs with the SDHB germline mutations of L157X and P236S. METHODS: Immunohistochemistry for SDHB was performed in PGLs with the SDHB germline mutations of L157X and P236S. Five cases of sporadic PCC were subject to immunohistochemistry testing for SDHB. Normal tissue from the adrenal cortex adjacent to the sporadic PCC was used as the external positive control. RESULTS: Immunohistochemistry results were positive for SDHB in PGLs with the SDHB germline mutation of L157X and P236S, all five cases of sporadic PCC, and the adrenal cortex as the external positive control. CONCLUSION: Immunohistochemistry tests for SDHB showed positivity in PGLs associated with the SDHB germline mutations of L157X and P236S. Thus, immunohistochemistry testing for SDHB might not always reveal a surrogate marker in formal genetic testing of the SDH complex.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Biomarcadores Tumorais/metabolismo , Mutação em Linhagem Germinativa , Paraganglioma/genética , Coloração e Rotulagem/métodos , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo , Córtex Suprarrenal/metabolismo , Humanos , Imuno-Histoquímica , Resultados Negativos
5.
Medicine (Baltimore) ; 99(38): e22312, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32957395

RESUMO

RATIONALE: Immunotherapy and targeted therapy have attracted widespread attention in current clinical research, which could be considered as a good therapeutic option for treatment of refractory liver cancer. PATIENT CONCERNS: The patient was a 37-year-old man with hepatitis B virus (HBV) infection. He was presented with hepatalgia and discomfort. DIAGNOSIS: The computed tomography showed multiple intrahepatic masses, indicating primary liver cancer with multiple intrahepatic metastases. INTERVENTIONS: After failed transarterial chemoembolization therapy, he was initially treated with immunotherapy pembrolizumab plus angiogenesis inhibitor lenvatinib, and after 3 months of treatment, the condition improved. However, the disease subsequently progressed. The next-generation sequencing identified a BRCA2 germline mutation in this patient. A poly (ADP-ribose) polymerase inhibitor, olaparib, plus nivolumab therapy was started and achieved stable disease. OUTCOMES: The patient achieved stable disease and improvement in hepatalgia for 3 months after the combination treatment of Olaparib and nivolumab. CONCLUSION: We identified a BRCA2 germline mutation in a patient with liver cancer. Our findings could offer an alternative management for patients with liver cancer harboring germline BRCA2 mutation.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Nivolumabe/uso terapêutico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Evolução Fatal , Genes BRCA2 , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/genética , Masculino
6.
Lancet Oncol ; 21(10): 1269-1282, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32861273

RESUMO

BACKGROUND: BRCA1 or BRCA2-mutated breast cancers are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum agents owing to deficiency in homologous recombination repair of DNA damage. In this trial, we compared veliparib versus placebo in combination with carboplatin and paclitaxel, and continued as monotherapy if carboplatin and paclitaxel were discontinued before progression, in patients with HER2-negative advanced breast cancer and a germline BRCA1 or BRCA2 mutation. METHODS: BROCADE3 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 147 hospitals in 36 countries. Eligible patients (aged ≥18 years) had deleterious germline BRCA1 or BRCA2 mutation-associated, histologically or cytologically confirmed advanced HER2-negative breast cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received up to two previous lines of chemotherapy for metastatic disease. Patients were randomly assigned (2:1) by interactive response technology by means of permuted blocks within strata (block size of 3 or 6) to carboplatin (area under the concentration curve 6 mg/mL per min intravenously) on day 1 and paclitaxel (80 mg/m2 intravenously) on days 1, 8, and 15 of 21-day cycles combined with either veliparib (120 mg orally twice daily, on days -2 to 5) or matching placebo. If patients discontinued carboplatin and paclitaxel before progression, they could continue veliparib or placebo at an intensified dose (300 mg twice daily continuously, escalating to 400 mg twice daily if tolerated) until disease progression. Patients in the control group could receive open-label veliparib monotherapy after disease progression. Randomisation was stratified by previous platinum use, history of CNS metastases, and oestrogen and progesterone receptor status. The primary endpoint was investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy analyses were done by intention to treat, which included all randomly assigned patients with a centrally confirmed BRCA mutation, and safety analyses included all patients who received at least one dose of velilparib or placebo. This study is ongoing and is registered with ClinicalTrials.gov, NCT02163694. FINDINGS: Between July 30, 2014, and Jan 17, 2018, 2202 patients were screened, of whom 513 eligible patients were enrolled and randomly assigned. In the intention-to-treat population (n=509), 337 patients were assigned to receive veliparib plus carboplatin-paclitaxel (veliparib group) and 172 were assigned to receive placebo plus carboplatin-paclitaxel (control group). Median follow-up at data cutoff (April 5, 2019) was 35·7 months (IQR 24·9-43·6) in the veliparib group and 35·5 months (23·1-45·9) in the control group. Median progression-free survival was 14·5 months (95% CI 12·5-17·7) in the veliparib group versus 12·6 months (10·6-14·4) in the control group (hazard ratio 0·71 [95% CI 0·57-0·88], p=0·0016). The most common grade 3 or worse adverse events were neutropenia (272 [81%] of 336 patients in the veliparib group vs 143 [84%] of 171 patients in the control group), anaemia (142 [42%] vs 68 [40%]), and thrombocytopenia (134 [40%] vs 48 [28%]). Serious adverse events occurred in 115 (34%) patients in the veliparib group versus 49 (29%) patients in the control group. There were no study drug-related deaths. INTERPRETATION: The addition of veliparib to a highly active platinum doublet, with continuation as monotherapy if the doublet were discontinued, resulted in significant and durable improvement in progression-free survival in patients with germline BRCA mutation-associated advanced breast cancer. These data indicate the utility of combining platinum and PARP inhibitors in this patient population. FUNDING: AbbVie.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carboplatina/uso terapêutico , Paclitaxel/uso terapêutico , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Método Duplo-Cego , Esquema de Medicação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Intervalo Livre de Progressão , Resultado do Tratamento
8.
Lancet Oncol ; 21(9): 1155-1164, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32771088

RESUMO

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors combined with immunotherapy have shown antitumour activity in preclinical studies. We aimed to assess the safety and activity of olaparib in combination with the PD-L1-inhibitor, durvalumab, in patients with germline BRCA1-mutated or BRCA2-mutated metastatic breast cancer. METHODS: The MEDIOLA trial is a multicentre, open-label, phase 1/2, basket trial of durvalumab and olaparib in solid tumours. Patients were enrolled into four initial cohorts: germline BRCA-mutated, metastatic breast cancer; germline BRCA-mutated, metastatic ovarian cancer; metastatic gastric cancer; and relapsed small-cell lung cancer. Here, we report on the cohort of patients with breast cancer. Patients who were aged 18 years or older (or aged 19 years or older in South Korea) with germline BRCA1-mutated or BRCA2-mutated or both and histologically confirmed, progressive, HER2-negative, metastatic breast cancer were enrolled from 14 health centres in the UK, the USA, Israel, France, Switzerland, and South Korea. Patients should not have received more than two previous lines of chemotherapy for metastatic breast cancer. Patients received 300 mg olaparib in tablet form orally twice daily for 4 weeks and thereafter a combination of olaparib 300 mg twice daily and durvalumab 1·5 g via intravenous infusion every 4 weeks until disease progression. Primary endpoints were safety and tolerability, and 12-week disease control rate. Safety was analysed in patients who received at least one dose of study treatment, and activity analyses were done in the full-analysis set (patients who received at least one dose of study treatment and were not excluded from the study). Recruitment has completed and the study is ongoing. This trial is registered with ClinicalTrials.gov, NCT02734004. FINDINGS: Between June 14, 2016, and May 2, 2017, 34 patients were enrolled and received both study drugs and were included in the safety analysis. 11 (32%) patients experienced grade 3 or worse adverse events, of which the most common were anaemia (four [12%]), neutropenia (three [9%]), and pancreatitis (two [6%]). Three (9%) patients discontinued due to adverse events and four (12%) patients experienced a total of six serious adverse events. There were no treatment-related deaths. 24 (80%; 90% CI 64·3-90·9) of 30 patients eligible for activity analysis had disease control at 12 weeks. INTERPRETATION: Combination of olaparib and durvalumab showed promising antitumour activity and safety similar to that previously observed in olaparib and durvalumab monotherapy studies. Further research in a randomised setting is needed to determine predictors of therapeutic benefit and whether addition of durvalumab improves long-term clinical outcomes compared with olaparib monotherapy. FUNDING: AstraZeneca.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/tratamento farmacológico , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Adulto Jovem
9.
PLoS Genet ; 16(8): e1008915, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776928

RESUMO

Sequences homologous to human herpesvirus 6 (HHV-6) are integrated within the nuclear genome of about 1% of humans, but it is not clear how this came about. It is also uncertain whether integrated HHV-6 can reactivate into an infectious virus. HHV-6 integrates into telomeres, and this has recently been associated with polymorphisms affecting MOV10L1. MOV10L1 is located on the subtelomere of chromosome 22q (chr22q) and is required to make PIWI-interacting RNAs (piRNAs). As piRNAs block germline integration of transposons, piRNA-mediated repression of HHV-6 integration has been proposed to explain this association. In vitro, recombination of the HHV-6 genome along its terminal direct repeats (DRs) leads to excision from the telomere and viral reactivation, but the expected "solo-DR scar" has not been described in vivo. Here we screened for integrated HHV-6 in 7,485 Japanese subjects using whole-genome sequencing (WGS). Integrated HHV-6 was associated with polymorphisms on chr22q. However, in contrast to prior work, we find that the reported MOV10L1 polymorphism is physically linked to an ancient endogenous HHV-6A variant integrated into the telomere of chr22q in East Asians. Unexpectedly, an HHV-6B variant has also endogenized in chr22q; two endogenous HHV-6 variants at this locus thus account for 72% of all integrated HHV-6 in Japan. We also report human genomes carrying only one portion of the HHV-6B genome, a solo-DR, supporting in vivo excision and possible viral reactivation. Together these results explain the recently-reported association between integrated HHV-6 and MOV10L1/piRNAs, suggest potential exaptation of HHV-6 in its coevolution with human chr22q, and clarify the evolution and risk of reactivation of the only intact (non-retro)viral genome known to be present in human germlines.


Assuntos
Genoma Humano , Herpesvirus Humano 6/genética , Integração Viral , Grupo com Ancestrais do Continente Asiático/genética , Cromossomos Humanos Par 22/genética , Evolução Molecular , Mutação em Linhagem Germinativa , Humanos , Polimorfismo de Nucleotídeo Único , RNA Interferente Pequeno/genética
10.
Mol Biol (Mosk) ; 54(4): 688-698, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32840490

RESUMO

A majority of BRCA1/2 (BRCA) pathogenic variants (PVs) are single nucleotide substitutions or small insertions/deletions. Copy number variations (CNVs), also known as large genomic rearrangements (LGRs), have been identified in BRCA genes. LGRs detection is a mandatory analysis in hereditary breast and ovarian cancer families, if no predisposing PVs are found by sequencing. Next generation sequencing (NGS) may be used to detect structural variation, since quantitative analysis of sequencing reads, when coupled with appropriate bioinformatics tools, is capable of estimating and predicting germline LGRs (gLGRs). However, applying this approach to tumor tissue is challenging, and the pipelines for determination of CNV are yet to be optimized. The aim of this study was to validate the Next Generation Tumor Sequencing (NGTS) technology to detect various gLGRs of BRCA1 locus in surgical tumor tissue samples. In this study, seven different BRCA1 gLGRs, previously found in high-grade serous ovarian cancers (HGSOC) patients, were detected in tumor samples collected from the patients at a time of HGSOC surgery. This study demonstrated that NGS can accurately detect BRCA1 gLGRs in primary tumors, suggesting that gLGR evaluation in BRCA1 locus should be performed in cases when the screening for BRCA alterations starts from tumor instead of blood. NGS sequencing of tumor samples may become the preferred method to detect both somatic and germline gLGRs in BRCA-encoding loci.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Genes BRCA1 , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias Ovarianas/genética , Variações do Número de Cópias de DNA/genética , Feminino , Células Germinativas/metabolismo , Mutação em Linhagem Germinativa , Humanos
11.
PLoS Biol ; 18(8): e3000838, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32804933

RESUMO

In humans, most germline mutations are inherited from the father. This observation has been widely interpreted as reflecting the replication errors that accrue during spermatogenesis. If so, the male bias in mutation should be substantially lower in a closely related species with similar rates of spermatogonial stem cell divisions but a shorter mean age of reproduction. To test this hypothesis, we resequenced two 3-4 generation nuclear families (totaling 29 individuals) of olive baboons (Papio anubis), who reproduce at approximately 10 years of age on average, and analyzed the data in parallel with three 3-generation human pedigrees (26 individuals). We estimated a mutation rate per generation in baboons of 0.57×10-8 per base pair, approximately half that of humans. Strikingly, however, the degree of male bias in germline mutations is approximately 4:1, similar to that of humans-indeed, a similar male bias is seen across mammals that reproduce months, years, or decades after birth. These results mirror the finding in humans that the male mutation bias is stable with parental ages and cast further doubt on the assumption that germline mutations track cell divisions. Our mutation rate estimates for baboons raise a further puzzle, suggesting a divergence time between apes and Old World monkeys of 65 million years, too old to be consistent with the fossil record; reconciling them now requires not only a slowdown of the mutation rate per generation in humans but also in baboons.


Assuntos
Mutação em Linhagem Germinativa , Hominidae/genética , Taxa de Mutação , Papio/genética , Reprodução/genética , Espermatozoides/metabolismo , Fatores Etários , Animais , Evolução Biológica , Divisão Celular , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Modelos Genéticos , Linhagem , Fatores Sexuais , Especificidade da Espécie , Espermatogênese/genética , Espermatozoides/citologia
16.
Eur J Endocrinol ; 183(4): 369-379, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32621582

RESUMO

Background: The '3PAs' syndrome, associating pituitary adenoma (PA) and pheochromocytoma/paraganglioma (PPGL), is sometimes associated with mutations in PPGL-predisposing genes, such as SDHx or MAX. In '3PAs' syndrome, PAs can occur before PPGL, suggesting a new gateway into SDHx/MAX-related diseases. Objective: To determine the SDHx/MAX mutation prevalence in patients with isolated PAs and characterize PAs of patients with SDHx/MAX mutations. Design: Genes involved in PAs (AIP/MEN1/CDKN1B) or PPGLs (SDHx/MAX) were sequenced in patients with isolated PAs. We then conducted a review of cases of PA in the setting of '3PAs' syndrome. Results: A total of 263 patients were recruited. Seven (likely) pathogenic variants were found in AIP, two in MEN1, two in SDHA, and one in SDHC. The prevalence of SDHx mutations reached 1.1% (3/263). Of 31 reported patients with PAs harboring SDHx/MAX mutations (28 published cases and 3 cases reported here), 6/31 (19%) developed PA before PPGL and 8/31 (26%) had isolated PA. The age of onset was later than in patients with AIP/MEN1 mutations. PAs were mainly macroprolactinomas and showed intracytoplasmic vacuoles seen on histopathology. Conclusions: We discovered SDHx mutations in patients bearing PA who had no familial or personal history of PPGL. However, the question of incidental association remains unresolved and data to determine the benefit of SDHx/MAX screening in these patients are lacking. We recommend that patients with isolated PA should be carefully examined for a family history of PPGLs. A family history of PPGL, as well as the presence of intracytoplasmic vacuoles in PA, requires SDHx/MAX genetic testing of patients.


Assuntos
Adenoma/genética , Mutação em Linhagem Germinativa , Neoplasias Hipofisárias/genética , Succinato Desidrogenase/genética , Adenoma/epidemiologia , Adenoma/patologia , Adolescente , Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idade de Início , Idoso , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Criança , Análise Mutacional de DNA/métodos , Feminino , França/epidemiologia , Predisposição Genética para Doença , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Isoenzimas/genética , Masculino , Pessoa de Meia-Idade , Paraganglioma/epidemiologia , Paraganglioma/genética , Paraganglioma/patologia , Feocromocitoma/epidemiologia , Feocromocitoma/genética , Feocromocitoma/patologia , Neoplasias Hipofisárias/epidemiologia , Neoplasias Hipofisárias/patologia , Prolactinoma/epidemiologia , Prolactinoma/genética , Prolactinoma/patologia , Subunidades Proteicas/genética , Estudos Retrospectivos , Adulto Jovem
17.
Gan To Kagaku Ryoho ; 47(7): 1113-1115, 2020 Jul.
Artigo em Japonês | MEDLINE | ID: mdl-32668864

RESUMO

Here, we report about a woman in her 30s who had peritoneal dissemination and multiple colon cancer with high-frequency microsatellite instability(MSI-H). Her father, paternal grandfather, and maternal grandmother had a history of colorectal cancer treatment. Thus, Lynch syndrome was suspected. We performed R0 resection for peritoneal dissemination and subsequent peritoneal dissemination. A 435-gene panel testing using a next-generation sequencer identified MSH2 and other mutations in the tumor. Hence, we speculated that she could have a germline mutation of MSH2, which causes Lynch syndrome. In the future, if she wishes to receive genetic counseling and undergo germline testing for variants to confirm the diagnosis of Lynch syndrome, we will perform them after receiving informed consent.


Assuntos
Neoplasias do Colo , Proteína 2 Homóloga a MutS/genética , Adulto , Neoplasias do Colo/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Instabilidade de Microssatélites , Proteína 1 Homóloga a MutL
19.
Rinsho Ketsueki ; 61(6): 687-696, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32624544

RESUMO

The RUNX1 gene is a critical transcription factor for the generation and maintenance of hematopoietic stem cells. RUNX1 is also one of the most frequently mutated gene in sporadic leukemias. Heterozygous loss-of-function mutations of the RUNX1 gene in the germline cause a rare autosomal dominant disorder called familial platelet disorder with propensity to acute myelogenous leukemia (FPD/AML). Besides the preexisting platelet disorder in FPD/AML patients, AML also develops in 20-60% of affected individuals. Since its discovery by the Gilliland group in 1999, RUNX1 mutation in the germline has been extensively investigated in the field. The past two decades of research have taught us three important lessons: 1) patients with FPD/AML display atypical symptoms and they have a widened clinical spectrum of FPD, such as eczema and syndromic thrombocytopenia, 2) the elucidation of variant of uncertain significance (VUS) of RUNX1 have revealed their role in epigenetic functions and involvement in the Fanconi anemia DNA repair pathway, and 3) non-coding mutations of RUNX1 also causes FPD/AML. In three distinct familial cases, an enhancer for RUNX1, eR1, was either lost or disconnected from the promoter through genetic deletion or chromosomal translocation abnormalities. This experience, with congenital mutations of RUNX1, will be very useful for future research for a series of other leukemia-causing germline mutations that have been recently identified.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda , Células Germinativas , Mutação em Linhagem Germinativa , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Linhagem
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