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1.
Breast Cancer Res Treat ; 207(3): 615-624, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38874686

RESUMO

PURPOSE: To define the spectrum of germline pathogenic variants (PVs) and copy number variant (CNV) in cancer susceptibility genes to the burden of breast and ovarian cancer (BC, OvC) in high-risk Brazilians in Minas Gerais with health insurance, southeast Brazil, undergoing multigene panel testing (MGPT). METHODS: Genotyping eligible individuals with health insurance in the Brazilian healthcare system for Hereditary Breast and Ovarian Cancer Syndrome to undergo molecular testing for 44 or 141-gene panels, a decision that was insurance driven. RESULTS: Overall, 701 individuals clinically defined as high BC/OvC risk, underwent MGPT from 1/2021 to 10/2022, with ~ 50% genotyped with a 44-gene panel and the rest with a 141-gene panel. Overall, 16.4% and 22.6% of genotyped individuals harbored PVs using 44-gene and the 141 gene panel, respectively. The most frequently mutated genes were: BRCA2 (3.7%); BRCA1 (3.6%) and monoallelic MUTYH (3.1%). CONCLUSION: The rate of PVs detected in high-risk individuals in this study was twice the 10% threshold used in Brazilian health guidelines. MGPT doubled the detection rate of PVs in cancer susceptibility genes in high-risk individuals compared with BRCA1/BRCA2 genotyping alone. The spectrum of PVs in Southern Brazil is diverse, with few recurring variants such as TP53 (0.6%), suggesting regional founder effects. The use of MGPT in hereditary cancer in Minas Gerais significantly increased the detection rate of P/LPVs compared to existing guidelines and should be considered as the primary genotyping modality in assessing hereditary cancer risk in Brazil.


Assuntos
Predisposição Genética para Doença , Testes Genéticos , Mutação em Linhagem Germinativa , Humanos , Feminino , Brasil/epidemiologia , Pessoa de Meia-Idade , Adulto , Testes Genéticos/métodos , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Variações do Número de Cópias de DNA , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/patologia , Idoso , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Genótipo , Proteína BRCA1/genética , DNA Glicosilases
2.
Mol Psychiatry ; 28(2): 553-563, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-35701598

RESUMO

People recovered from COVID-19 may still present complications including respiratory and neurological sequelae. In other viral infections, cognitive impairment occurs due to brain damage or dysfunction caused by vascular lesions and inflammatory processes. Persistent cognitive impairment compromises daily activities and psychosocial adaptation. Some level of neurological and psychiatric consequences were expected and described in severe cases of COVID-19. However, it is debatable whether neuropsychiatric complications are related to COVID-19 or to unfoldings from a severe infection. Nevertheless, the majority of cases recorded worldwide were mild to moderate self-limited illness in non-hospitalized people. Thus, it is important to understand what are the implications of mild COVID-19, which is the largest and understudied pool of COVID-19 cases. We aimed to investigate adults at least four months after recovering from mild COVID-19, which were assessed by neuropsychological, ocular and neurological tests, immune markers assay, and by structural MRI and 18FDG-PET neuroimaging to shed light on putative brain changes and clinical correlations. In approximately one-quarter of mild-COVID-19 individuals, we detected a specific visuoconstructive deficit, which was associated with changes in molecular and structural brain imaging, and correlated with upregulation of peripheral immune markers. Our findings provide evidence of neuroinflammatory burden causing cognitive deficit, in an already large and growing fraction of the world population. While living with a multitude of mild COVID-19 cases, action is required for a more comprehensive assessment and follow-up of the cognitive impairment, allowing to better understand symptom persistence and the necessity of rehabilitation of the affected individuals.


Assuntos
COVID-19 , Disfunção Cognitiva , Adulto , Humanos , COVID-19/complicações , Neuroimagem , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico , Imageamento por Ressonância Magnética
3.
Acta Paediatr ; 113(6): 1420-1425, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38363039

RESUMO

AIM: This study reports the bilateral association of Peters' anomaly and congenital aniridia in monozygotic twins subsequently diagnosed with Wilms tumour (WAGR syndrome). METHODS: Two monozygotic female twins were referred at age 2 months with bilateral corneal opacity. A diagnosis of Peters' anomaly associated to aniridia was made in both eyes of both twins. Physical examination and ultrasonography were carried out at 12 months of age to explore the possibility of WAGR-related anomalies, specifically Wilms tumour. DNA were isolated and subjected to whole exome sequencing. RESULTS: Peters' anomaly associated to aniridia in both eyes as well as bilateral Wilms tumour in both children were diagnosed. Exome analyses showed a large heterozygous deletion encompassing 6 648 473 bp in chromosome 11p13, using Integrative Genomics Viewer and AnnotSV software. CONCLUSION: WAGR syndrome is a rare contiguous gene deletion syndrome with a greater risk of developing Wilms tumour associated with Peters' anomaly and congenital aniridia. However, co-occurrence of both anomalies was rarely reported in twins, and never in both eyes of monozygotic twins. Here, we report the bilateral association of Peters' anomaly and congenital aniridia in monozygotic twins with WAGR syndrome.


Assuntos
Aniridia , Opacidade da Córnea , Gêmeos Monozigóticos , Síndrome WAGR , Tumor de Wilms , Humanos , Feminino , Gêmeos Monozigóticos/genética , Síndrome WAGR/genética , Aniridia/genética , Aniridia/complicações , Tumor de Wilms/genética , Tumor de Wilms/complicações , Lactente , Opacidade da Córnea/genética , Segmento Anterior do Olho/anormalidades , Segmento Anterior do Olho/diagnóstico por imagem , Anormalidades do Olho/genética , Anormalidades do Olho/diagnóstico por imagem , Anormalidades do Olho/complicações , Doenças em Gêmeos/genética , Neoplasias Renais/genética , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/complicações
4.
J Oral Pathol Med ; 52(6): 548-553, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36504219

RESUMO

BACKGROUND: Respiratory epithelial adenomatoid hamartoma (REAH) is a sinonasal glandular overgrowth arising from the surface respiratory epithelium and invaginating into the stroma. Clinically, it appears as a polypoid mass that may cause nasal obstruction, anosmia, and epistaxis. The presence of cartilaginous and/or osseous areas move the lesion to a chondro-osseous respiratory epithelial (CORE) hamartoma subtype. Scattered small seromucinous glands may be observed between typical REAH glands and when it is the only feature, it represents seromucinous hamartoma (SH). The molecular pathogenesis of REAH has been poorly explored and remains unclear. Given that KRAS, BRAF, and EGFR mutations have been detected in a variety of sinonasal tumors, we aimed to assess these mutations in REAH and SH. METHODS: Ten REAH (including one CORE subtype), in addition to two SH cases, were Sanger sequenced by standard techniques. The targeted regions included KRAS exons 2-4 (encompassing hotspots codons 12, 13, 61, and 146), BRAF exons 11 and 15 (spanning the V600 codon), and EGFR exons 19 and 20. RESULTS: All REAH and SH samples showed wild-type sequences for KRAS, BRAF, and EGFR genes. CONCLUSION: Our results demonstrate a lack of KRAS, BRAF, or EGFR pathogenic variants with further evaluation of REAH and SH needed to elucidate driver genetic events.


Assuntos
Adenoma , Hamartoma , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Mucosa Respiratória/patologia , Adenoma/patologia , Hamartoma/genética , Hamartoma/diagnóstico , Hamartoma/patologia , Receptores ErbB/genética , Diagnóstico Diferencial
5.
J Oral Pathol Med ; 52(5): 426-430, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36116035

RESUMO

BACKGROUND: Chronic rhinosinusitis is a chronic inflammation of the nasal mucosa and nasal polyps are present in ~25%-30% of cases (chronic rhinosinusitis with nasal polyps [CRSwNP]). CRSwNP is associated with significant morbidity and decreased quality of life, making it clinically important. Inflammation leads to DNA damage and DNA mutations occur in some inflammatory diseases. Notably, mutations in KRAS, BRAF, and EGFR have been reported in different human benign and malignant neoplastic lesions. In addition, KRAS mutations have also been reported in non-neoplastic tissues under chronic inflammatory conditions. Importantly, KRAS mutations have been reported in oncocytic sinonasal papillomas and sinonasal squamous cell carcinoma associated with oncocytic sinonasal papilloma and EGFR mutations have been reported in sinonasal adenocarcinoma, inverted sinonasal papilloma, and sinonasal squamous cell carcinoma associated with inverted sinonasal papilloma. The molecular pathogenesis of nasal polyps remains unclear. Therefore, the present study aimed to investigate the presence of KRAS, BRAF, and EGFR pathogenic mutations in CRSwNP. METHODS: Fourteen chronic rhinosinusitis-associated nasal polyp samples were direct sequenced, targeting KRAS exons 2, 3, and 4 (encompassing important hotspot mutations, including codons 12, 13, 61 and 146), BRAF exons 11 and 15, and EGFR exons 19 and 20. RESULTS: No pathogenic mutations were detected in the sequenced regions of KRAS, BRAF, and EGFR genes. CONCLUSION: This finding suggests that mutations in these genes are not a frequent event in CRSwNP, and, if they occur, they might represent marginal events at best.


Assuntos
Neoplasias de Cabeça e Pescoço , Pólipos Nasais , Papiloma , Sinusite , Humanos , Pólipos Nasais/complicações , Pólipos Nasais/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Qualidade de Vida , Mutação , Sinusite/complicações , Sinusite/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço , Papiloma/genética , Inflamação , Receptores ErbB/genética , Doença Crônica
6.
J Oral Pathol Med ; 52(3): 271-275, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36169975

RESUMO

BACKGROUND: TERT promoter mutations increase telomerase activity, conferring cell immortality. The coexistence of TERT promoter mutations with BRAFV600E is associated with aggressiveness. Ameloblastoma and ameloblastic carcinoma are infiltrative neoplasms that harbor BRAFV600E; however, it remains unknown if these odontogenic tumors also show TERT promoter mutations. METHODS: Genomic DNA of paraffin-embedded ameloblastomas (n = 6) and ameloblastic carcinomas (n = 3) were Sanger-sequenced to assess the hotspot TERT promoter mutations C228T and C250T. BRAFV600E status was screened by TaqMan allele-specific quantitative polymerase chain reaction. RESULTS: None of the samples harbored TERT promoter mutations. The BRAFV600E mutation was positive in 3 of 6 of ameloblastomas and in 1 of 3 of ameloblastic carcinomas. CONCLUSION: The absence of TERT promoter mutation in the samples indicates that this molecular event is not relevant to the tumors' pathogenesis. Further studies are necessary to explore undefined genetic or epigenetic mechanisms related to TERT-upregulation in ameloblastoma, and the telomerase activity in ameloblastic carcinoma.


Assuntos
Ameloblastoma , Carcinoma , Tumores Odontogênicos , Telomerase , Humanos , Ameloblastoma/genética , Telomerase/genética , Telomerase/metabolismo , Tumores Odontogênicos/genética , Mutação
7.
Mod Pathol ; 35(11): 1562-1569, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35840721

RESUMO

Adenoid ameloblastoma is a very rare benign epithelial odontogenic tumor characterized microscopically by epithelium resembling conventional ameloblastoma, with additional duct-like structures, epithelial whorls, and cribriform architecture. Dentinoid deposits, clusters of clear cells, and ghost-cell keratinization may also be present. These tumors do not harbor BRAF or KRAS mutations and their molecular basis appears distinct from conventional ameloblastoma but remains unknown. We assessed CTNNB1 (beta-catenin) exon 3 mutations in a cohort of 11 samples of adenoid ameloblastomas from 9 patients. Two of the 9 patients were female and 7 male and in 7/9 patients the tumors occurred in the maxilla. Tumors of 4 of these 9 patients harbored CTNNB1 mutations, specifically p.Ser33Cys, p.Gly34Arg, and p.Ser37Phe. Notably, for one patient 3 samples were analyzed including the primary tumour and two consecutive recurrences, and results were positive for the mutation in all three tumors. Therefore, 6/11 samples tested positive for the mutation. In the 6 mutation-positive samples, ghost cells were present in only 2/6, indicating beta-catenin mutations are not always revealed by ghost cell formation. Dentinoid matrix deposition was observed in 5/6 mutation-positive samples and clear cells in all 6 cases. None of the cases harbored either BRAF or KRAS mutations. Beta-catenin immunoexpression was assessed in the samples of 8 patients. Except for one wild-type case, all cases showed focal nuclear expression irrespective of the mutational status. Together with the absence of BRAF mutation, the detection of beta-catenin mutation in adenoid ameloblastomas supports its classification as a separate entity, and not as a subtype of ameloblastoma. The presence of this mutation may help in the diagnosis of challenging cases.


Assuntos
Tonsila Faríngea , Ameloblastoma , Tumores Odontogênicos , Humanos , Masculino , Feminino , Ameloblastoma/genética , Ameloblastoma/patologia , beta Catenina/genética , beta Catenina/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Tonsila Faríngea/metabolismo , Tonsila Faríngea/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Tumores Odontogênicos/patologia , Mutação
8.
J Oral Pathol Med ; 51(4): 405-412, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35103997

RESUMO

BACKGROUND: Fibrous dysplasia (FD) and cemento-ossifying fibroma (COF) are the most common gnathic fibro-osseous lesions. These diseases exhibit remarkable overlap of several clinicopathological aspects, and differential diagnosis depends on the combination of histopathological, radiographic, and clinical aspects. Their molecular landscape remains poorly characterized, and herein, we assessed their proteomic and phosphoproteomic profiles. METHODS: The quantitative differences in protein profile of FD and COF were assessed by proteomic and phosphoproteomic analyses of formalin-fixed paraffin-embedded tissue samples. Pathway enrichment analyses with differentially regulated proteins were performed. RESULTS: FD and COF exhibited differential regulation of pathways related to extracellular matrix organization, cell adhesion, and platelet and erythrocytes activities. Additionally, these lesions demonstrated distinct abundance of proteins involved in osteoblastic differentiation and tumorigenesis and differential abundance of phosphorylation of Ser61 of Yes-associated protein 1 (YAP1). CONCLUSIONS: In summary, despite the morphological similarity between these diseases, our results demonstrated that COF and DF present numerous quantitative differences in their proteomic profiles. These findings suggest that these fibro-osseous lesions trigger distinct molecular mechanisms during their pathogenesis. Moreover, some proteins identified in our analysis could serve as potential biomarkers for differential diagnosis of these diseases after further validation.


Assuntos
Cementoma , Fibroma Ossificante , Displasia Fibrosa Óssea , Cementoma/diagnóstico , Cementoma/patologia , Diagnóstico Diferencial , Fibroma Ossificante/metabolismo , Displasia Fibrosa Óssea/patologia , Humanos , Proteômica
9.
Genes Chromosomes Cancer ; 59(9): 503-516, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32337806

RESUMO

Activating point mutations in two codons (R201 and Q227) in the alpha subunit of the stimulatory GTP binding protein (GNAS) gene-coined gsp mutations-were originally reported in growth hormone secreting pituitary adenomas. In these tumor types, gsp activating mutations were associated with uncontrolled intracellular cAMP accumulation leading to cellular proliferation and tumor formation. Since the original description of gsp mutations in pituitary and later thyroid neoplasia, many more tumors were genotyped for these specific activating mutations. In this paradigm, GNAS is an oncogene that can be activated by other molecular mechanisms, such as DNA amplification and translocation. Herein, we describe the largest account to date of tumor types that harbor pathogenic GNAS genomic alterations (GAs) including the "classical" gsp activating point mutations, delineate some common features of these tumors, and speculate as to the possible mechanisms whereby GNAS activating GAs are associated with the various stages of tumorigenesis.


Assuntos
Cromograninas/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Neoplasias/genética , Dosagem de Genes , Frequência do Gene , Rearranjo Gênico , Humanos , Mutação Puntual
10.
J Oral Pathol Med ; 48(5): 421-423, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30849196

RESUMO

Chronic mucosal trauma is suggested as an additional etiologic risk factor for oral squamous cell carcinoma (OSCC), but there is a lack of experimental-molecular data. If chronic trauma of the oral mucosa is carcinogenic, it should be associated with early genetic alterations seen during typical progression of OSCC, like loss of heterozygosity (LOH). We investigated LOH in the key chromosomal arms 3p, 9p and 17p in inflammatory fibrous hyperplasia associated with removable dental prosthesis and also in normal oral mucosa, by using the polymorphic microsatellite markers D3S1300 at 3p14.2, D9S1748 at 9p21, D17S1289 at 17p12 and D17S974 at 17p13 and capillary electrophoresis. LOH was detected in 2/15 (13%) fibrous hyperplasia samples similarly to other reactive and inflammatory lesions. None of the normal mucosa samples presented LOH. Our experimental-molecular results do not support the hypothesis that trauma associated with dental prosthesis has an important role in oral carcinogenesis.


Assuntos
Carcinoma de Células Escamosas/complicações , Dentaduras/efeitos adversos , Perda de Heterozigosidade , Neoplasias Bucais/complicações , Boca/lesões , Adulto , Idoso , Carcinogênese , Cromossomos Humanos Par 17 , Cromossomos Humanos Par 3 , Cromossomos Humanos Par 9 , Feminino , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade
11.
Carcinogenesis ; 38(11): 1112-1118, 2017 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-28968711

RESUMO

Lung cancer (LC) is a leading cause of cancer-related mortality. Although smoking is the major risk factor, ~15% of all cases occur in never-smokers, suggesting that genetic factors play a role in LC predisposition. Indeed, germline mutations in the TP53 gene predispose to multiple cancer types, including LC. To date, few studies compared the somatic and germline mutational profiles of LC cases by smoking status, and none was reported in Brazilians. Whole-exome sequencing (WES) was performed on two pools (seven smokers and six non-smokers) of tumor-derived DNA using the Illumina HiSeq2000 platform. Files from pools were analyzed separately using Ingenuity®Variant AnalysisTM and Mendel,MD. Validation of all candidate variants was performed by Sanger sequencing. Subsequently, validated mutations were analyzed in germline DNA from the same patients and in ethnically matched controls. In addition, a single recurring Brazilian TP53 germline mutation (R337H) was genotyped in 45 non-small-cell lung cancer patients.Four novel germline variants in the ATAD2, AURKA, PTPRD and THBS1 genes were identified exclusively in smoker patients, and four germline missense variants in PLCD1, RAD52, CP and CDC6 genes were identified solely in non-smokers. There were 4/45 (8.9%) germline carriers of the R337H TP53 mutation. In conclusion, the recurring Brazilian TP53 mutation should be genotyped in all non-small-cell lung cancer in Brazil, regardless of smoking status. Distinct pathogenic mutations and novel sequence variants are detected in Brazilian non-small-cell lung cancer patients, by smoking status. The contribution of these sequence variants to LC pathogenesis remains to be further explored.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Mutação em Linhagem Germinativa/genética , Neoplasias Pulmonares/genética , Fumar/genética , Adulto , Idoso , Brasil , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Proteína Supressora de Tumor p53/genética
12.
Phytother Res ; 31(10): 1607-1613, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28816367

RESUMO

Angiogenesis is implicated in the development of a variety of pathological processes, most commonly cancer. It is essential for tumor growth and metastasis, making it an important cancer therapeutic target. Naturally occurring substances have led to the discovery of anticancer agents. Flavokawain B (FKB), a chalcone isolated from the root extracts of kava-kava plant, inhibits proliferation and causes apoptosis in vitro and in vivo of various cancer cell lines. The antimetastatic potential of FKB has also been suggested. In our study, we confirm the antiangiogenic action of FKB in vitro and, for the first time, demonstrate its strong antiangiogenic activity in vivo, using a zebrafish model. Our data show that FKB inhibits human brain endothelial cell (HUVEC) migration and tube formation even at very low and non-toxic concentrations. Moreover, FKB blocks angiogenesis process in zebrafish, with a dramatic reduction of subintestinal vein formation in a dose-dependent manner. Flavokawain B at the concentration of 2.5 µg/mL did not exhibit any toxic effects in zebrafish larvae and caused a markedly or complete obliteration of subintestinal vein formation. Our findings along with previously published data confirm that FKB may form the basis for creating an additional tool in the treatment of cancer and other neovascularization-related diseases. Copyright © 2017 John Wiley & Sons, Ltd.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Flavonoides/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Chalcona/farmacologia , Embrião não Mamífero/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Kava/química , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Peixe-Zebra
13.
Int J Geriatr Psychiatry ; 31(12): 1337-1344, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-26876984

RESUMO

OBJECTIVES: In 2012, Kamboh and colleagues published a genome-wide association study that identified the DCHS2 gene (rs1466662 T/A) influencing the age at onset of Alzheimer's disease (AD). We aimed to investigate if there is association between the DCHS2 gene and amnestic mild cognitive impairment (aMCI) and AD in a sample of the Brazilian population. METHODS: 143 controls, 79 aMCI and 299 AD patients were selected and submitted to the same protocol of tests. Genotyping was performed using the Real Time PCR RESULTS: Amnestic MCI patients showed a higher prevalence of AA than controls and a lower frequency of TT when compared with controls. We also stratified the sample according to the APOE ε4 status. No difference in DCHS2 genotype or allelic frequency occurred in the APOE ε4 allele carrier subgroup. Amnestic MCI patients showed a higher frequency of AA genotype and a lower frequency of TA and TT when compared with controls in APOE ε4 allele non-carrier subgroup. The allelic distribution followed the same pattern. In AD group, we observed a significant difference with a higher A allelic frequency in AD in this subgroup. A multiple logistic regression demonstrated that in APOE ε4 non-carriers, allele rs1466662 was associated to aMCI group. Different variables were associated with aMCI and AD according to APOE ε4 status in our sample. Low level of education was associated with AD, while diabetes mellitus type 2 was associated with aMCI. Copyright © 2016 John Wiley & Sons, Ltd. CONCLUSIONS: Our findings suggest a possible role for DCHS2 gene in aMCI and AD.


Assuntos
Doença de Alzheimer/genética , Caderinas/genética , Disfunção Cognitiva/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/etiologia , Brasil/epidemiologia , Estudos de Casos e Controles , Escolaridade , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Modelos Logísticos , Masculino , Fatores de Risco
14.
Genet Res (Camb) ; 97: e3, 2015 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-25819804

RESUMO

BACKGROUND: Paraganglioma syndrome type 1 (PGL1) is a rare autosomal dominant syndrome associated with multiple, overwhelmingly benign, pheochromocytomas and paragangliomas, attributed to SDHD gene mutations. OBJECTIVE: Clinically and molecularly characterize a family with uncommon malignant phenotype of paragangliomas attributed to two seemingly pathogenic SDHD germline mutations. MATERIALS & METHODS: The proband presented with large bilateral carotid body tumours and family history of cervical masses in his five siblings. All family members underwent clinical examination, imaging studies (18F-FDG PET/CT) and genotyping of relevant genes. The proband was diagnosed with locally advanced paraganglioma; his hypertensive, otherwise asymptomatic father, had locally advanced pheochromocytoma and his three siblings showed multiple head and neck masses, confirmed to be paragangliomas with local metastasis. All affected patients carried two germline mutations in the SDHD gene; a previously reported nonsense mutation in exon 1 (p.Trp5X) and a novel missense mutation in exon 2 (p.Pro53Leu), highly deleterious by in silico analysis. Allelic loss at the SDHD locus was not shown for any of the analysed tumours. CONCLUSIONS: This is a rare case of malignant PGL1 with seemingly double pathogenic mutations in the SDHD gene, highlighting the possibility that the presence of both mutations is associated with the more aggressive phenotype.


Assuntos
Predisposição Genética para Doença/genética , Mutação , Paraganglioma/genética , Feocromocitoma/genética , Succinato Desidrogenase/genética , Adulto , Sequência de Bases , Códon sem Sentido , Análise Mutacional de DNA , Saúde da Família , Evolução Fatal , Feminino , Genótipo , Mutação em Linhagem Germinativa , Humanos , Masculino , Mutação de Sentido Incorreto , Paraganglioma/patologia , Linhagem , Fenótipo , Feocromocitoma/patologia , Síndrome
15.
Int Psychogeriatr ; 27(10): 1687-92, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25853819

RESUMO

BACKGROUND: Evidences suggest that GAB2 and BDNF genes may be associated with Alzheimer's disease (AD). We aimed to investigate the GAB2 rs2373115 and BDNF rs6265 polymorphisms and the risk of AD in a Brazilian sample. METHODS: 269 AD patients and 114 controls were genotyped with Real-time PCR. Multifactor dimensionality reduction (MDR) was employed to explore the effects of gene-gene interactions. RESULTS: GAB2 and BDNF were not associated with AD in our sample. Nevertheless BDNF Val allele (rs6265) presented a synergic association with the APOE ε4 allele. A multiple logistic regression demonstrated that the APOE ε4 allele and years of education were the best predictors for AD. In ε4 non-carriers sex, education and hypertension were independently correlated with AD, while in ε4 carriers we did not observe any association. The findings were further confirmed by bootstrapping method. CONCLUSIONS: Our data suggest that the interaction of BDNF and APOE has significant effect on AD. Moreover in absence of ε4, female sex, low level of education and hypertension are independently associated with AD. Interventions aimed to prevent AD should focus on these factors and also taking into account the APOE alleles.


Assuntos
Doença de Alzheimer/genética , Apolipoproteína E4/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Brasil , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Fatores de Risco
16.
Genet Res (Camb) ; 96: e002, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24594201

RESUMO

Lung cancer is the leading global cause of cancer-related mortality. Inter-individual variability in treatment response and prognosis has been associated with genetic polymorphisms in specific genes: EGFR, KRAS, BRAF, PTEN and TTF-1. Somatic mutations in EGFR and KRAS genes are reported at rates of 15-40% in non-small cell lung cancer (NSCLC) in ethnically diverse populations. BRAF and PTEN are commonly mutated genes in various cancer types, including NSCLC, with PTEN mutations exerting an effect on the therapeutic response of EGFR/AKT/PI3K pathway inhibitors. TTF-1 is expressed in approximately 80% of lung adenocarcinomas and its positivity correlates with higher prevalence of EGFR mutation in this cancer type. To determine molecular markers for lung cancer in Brazilian patients, the rate of the predominant EGFR, KRAS, BRAF and PTEN mutations, as well as TTF-1 expression, was assessed in 88 Brazilian NSCLC patients. EGFR exon 19 deletions (del746-750) were detected in 3/88 (3·4%) patients. Activating KRAS mutations in codons 12 and 61 were noted in five (5·7%) and two (2·3%) patients, respectively. None of the common somatic mutations were detected in either the BRAF or PTEN genes. TTF-1 was overexpressed in 40·7% of squamous-cell carcinoma (SCC). Our findings add to a growing body of data that highlights the genetic heterogeneity of the abnormal EGFR pathway in lung cancer among ethnically diverse populations.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Mutação/genética , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Técnicas Imunoenzimáticas , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase , Prognóstico , Proteínas Proto-Oncogênicas p21(ras) , Fatores de Transcrição
17.
Malar J ; 13: 73, 2014 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-24581308

RESUMO

BACKGROUND: Chloroquine (CQ), a cost effective antimalarial drug with a relatively good safety profile and therapeutic index, is no longer used by itself to treat patients with Plasmodium falciparum due to CQ-resistant strains. P. vivax, representing over 90% of malaria cases in Brazil, despite reported resistance, is treated with CQ as well as with primaquine to block malaria transmission and avoid late P. vivax malaria relapses. Resistance to CQ and other antimalarial drugs influences malaria control, thus monitoring resistance phenotype by parasite genotyping is helpful in endemic areas. METHODS: A total of 47 P. vivax and nine P. falciparum fresh isolates were genetically characterized and tested for CQ, mefloquine (MQ) and artesunate (ART) susceptibility in vitro. The genes mdr1 and pfcrt, likely related to CQ resistance, were analyzed in all isolates. Drug susceptibility was determined using short-term parasite cultures of ring stages for 48 to 72 hour and thick blood smears counts. Each parasite isolate was tested with the antimalarials to measure the geometric mean of 50% inhibitory concentration. RESULTS: The low numbers of P. falciparum isolates reflect the species prevalence in Brazil; most displayed low sensitivity to CQ (IC50 70 nM). However, CQ resistance was rare among P. vivax isolates (IC50 of 32 nM). The majority of P. vivax and P. falciparum isolates were sensitive to ART and MQ. One hundred percent of P. falciparum isolates carried non-synonymous mutations in the pfmdr1 gene in codons 184, 1042 and 1246, 84% in codons 1034 and none in codon 86, a well-known resistance mutation. For the pfcrt gene, mutations were observed in codons 72 and 76 in all P. falciparum isolates. One P. falciparum isolate from Angola, Africa, showing sensitivity to the antimalarials, presented no mutations. In P. vivax, mutations of pvmdr1 and the multidrug resistance gene 1 marker at codon F976 were absent. CONCLUSION: All P. falciparum Brazilian isolates showed CQ resistance and presented non-synonymous mutations in pfmdr1 and pfcrt. CQ resistant genotypes were not present among P. vivax isolates and the IC50 values were low in all samples of the Brazilian West Amazon.


Assuntos
Antimaláricos/farmacologia , DNA de Protozoário/genética , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Plasmodium vivax/efeitos dos fármacos , Plasmodium vivax/genética , Adulto , Artemisininas/farmacologia , Artesunato , Brasil , Cloroquina/farmacologia , DNA de Protozoário/química , Resistência a Medicamentos , Feminino , Genótipo , Humanos , Concentração Inibidora 50 , Malária/parasitologia , Masculino , Mefloquina/farmacologia , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Mutação de Sentido Incorreto , Testes de Sensibilidade Parasitária , Plasmodium falciparum/isolamento & purificação , Plasmodium vivax/isolamento & purificação , Proteínas de Protozoários/genética
18.
Nephrology (Carlton) ; 19(11): 714-20, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24995698

RESUMO

AIM: The angiotensin type 2 (AT2 ) receptor takes part in the process of ureteric bud during kidney development. Therefore, the gene encoding AT2 receptor, the AGTR2 gene located in the X chromosome, is a potential candidate for genetic association with Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). This study aimed to investigate whether AGTR2 gene polymorphisms are associated with CAKUT in general or even with common phenotypes of CAKUT in a Brazilian sample of paediatric patients. METHODS: We analyzed 290 paediatric patients with CAKUT and 262 healthy controls from the same geographic area. TaqMan single-nucleotide polymorphism (SNP) genotyping assays for AGTR2 gene at rs1403543, rs3736556, rs35474657, rs5193 and rs5194 were performed. The sample was in Hardy-Weinberg Equilibrium for all five SNPs. RESULTS: The presence of CAKUT in general was not significantly associated with the SNPs included in this study. However, when patients were segregated according to major phenotypes, the diagnosis of Ureteropelvic Junction Obstruction (UPJO) was significantly associated with AGTR2 gene polymorphisms at rs3736556 and at rs5194. On the other hand, the diagnoses of vesicoureteral reflux and of multicystic dysplastic kidney were not associated with AGTR2 gene polymorphisms. CONCLUSION: Our results support that the AGTR2 gene may contribute to the pathogenesis of UPJO and the genetic origin of CAKUT could vary according to phenotype expression.


Assuntos
Hidronefrose/congênito , Rim Displásico Multicístico/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 2 de Angiotensina/genética , Obstrução Ureteral/genética , Brasil , Criança , Pré-Escolar , Feminino , Humanos , Hidronefrose/genética , Masculino , Fenótipo
19.
Ann Nutr Metab ; 65(4): 272-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25376908

RESUMO

BACKGROUND/AIMS: Berardinelli-Seip syndrome (BSS) is a recessive autosomal genetic disorder characterized by the near loss of adipose tissue with disturbance in lipid metabolism. METHODS: Biochemical and hormonal parameters and Pro12Ala, Pvull, Avall, Sstl and ADIPOQ polymorphisms in 22 patients with BSS were analyzed and examined for a possible association with lipid profiles. RESULTS: Parental consanguinity, insulin resistance and diabetes mellitus were observed in 63.6, 81.8 and 59.1% of patients, respectively. All individuals presented high triglyceride levels, and 68.1% of patients showed high cholesterol levels. The Pro/Pro genotype of the Pro12Ala polymorphism of the PPARγ2 gene was found in 86.3% of patients; the Ala/Ala variant was not observed in any patient. The PvuII polymorphism of the LPL gene showed a frequency of 50% for the P1P2 variant. The AvaII polymorphism of the LDLR gene showed a similar frequency of 40.9% for both CT and TT variants. The S1S1 genotype of the Sstl polymorphism of the APOC3 gene had a frequency of 86.3%. The CC allele of the ADIPOQ polymorphism of the adiponectin gene was found in 54.6% of patients. CONCLUSIONS: No association was found between lipid parameters and the relevant Pvull, Avall and Sstl polymorphisms. However, we did observe an association of the Pro12Ala and ADIPOQ polymorphisms with higher lipid levels, suggesting a close relationship between these factors.


Assuntos
Adiponectina/genética , Predisposição Genética para Doença , Lipodistrofia Generalizada Congênita/genética , PPAR gama/genética , Adulto , Brasil , Colesterol/sangue , Feminino , Humanos , Lipodistrofia Generalizada Congênita/sangue , Masculino , Polimorfismo de Nucleotídeo Único , Triglicerídeos/sangue , População Branca
20.
Case Rep Endocrinol ; 2024: 6664694, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39129823

RESUMO

The combination of clinical characteristics and diagnostic exams including imaging, laboratory, and molecular tests help in the differential diagnosis of retroperitoneal lesions. We report a 41-year-old male with a metastatic retroperitoneal lesion with atypical characteristics, displaying pathological findings consistent with both nonsecretory pheochromocytomas/paragangliomas and adrenal cortex carcinoma. The patient was examined for abdominal pain, weight loss, and hypertension. Abdominal computed tomography showed a 21 × 8 × 10-cm right retroperitoneal mass. He was initially diagnosed as pheochromocytoma/paraganglioma (PHEO/PGL). However, the diagnosis was later changed to adrenocortical carcinoma based on histopathological features of the metastatic lesions and the findings of normal urinary levels of catecholamines/metanephrines. Systemic chemotherapy and abdominal radiotherapy were performed, in addition to multiple surgical resections, with no satisfactory response. The indolent course of the disease and minimal impact on the patient's performance status led to a genetic evaluation which resulted in the identification of a germline mutation in the succinate dehydrogenase complex subunit B (SDHB). An immunohistology review of previous slides was consistent with the hypothesis of a neuroendocrine tumor. Forty percent of the patients with PHEO/PGL have an underlying germline mutation. SDHB mutation is frequently associated with metastatic disease and dominant secretion of noradrenaline and/or dopamine. In addition to the metastatic disease, few cases with the mutations can be a biochemically silent PHEO/PGL. We concluded that the patient presented a metastatic abdominal paraganglioma associated with an SDHB mutation and we reinforced the need to perform genetic screening for all adrenal/extra-adrenal lesions characteristic of PHEO/PGL.

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