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1.
Ophthalmology ; 127(5): 668-678, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32081490

RESUMO

PURPOSE: To identify susceptibility genes associated with hereditary predisposition to uveal melanoma (UM) in patients with no detectable germline BAP1 alterations. DESIGN: Retrospective case series from academic referral centers. PARTICIPANTS: Cohort of 154 UM patients with high risk of hereditary cancer defined as patients with 1 or more of the following: (1) familial UM, (2) young age (<35 years) at diagnosis, (3) personal history of other primary cancers, and (4) family history of 2 or more primary cancers with no detectable mutation or deletion in BAP1 gene. METHODS: Whole exome sequencing, a cancer gene panel, or both were carried out. Probands included 27 patients with familial UM, 1 patient with bilateral UM, 1 patient with congenital UM, and 125 UM patients with strong personal or family histories, or both, of cancer. Functional validation of variants was carried out by immunohistochemistry, reverse-transcriptase polymerase chain reaction, and genotyping. MAIN OUTCOME MEASURES: Clinical characterization of UM patients with germline alterations in known cancer genes. RESULTS: We identified actionable pathogenic variants in 8 known hereditary cancer predisposition genes (PALB2, MLH1, MSH6, CHEK2, SMARCE1, ATM, BRCA1, and CTNNA1) in 9 patients, including 3 of 27 patients (11%) with familial UM and 6 of 127 patients (4.7%) with a high risk for cancer. Two patients showed pathogenic variants in CHEK2 and PALB2, whereas variants in the other genes each occurred in 1 patient. Biallelic inactivation of PALB2 and MLH1 was observed in tumors from the respective patients. The frequencies of pathogenic variants in PALB2, MLH1, and SMARCE1 in UM patients were significantly higher than the observed frequencies in noncancer controls (PALB2: P = 0.02; odds ratio, 8.9; 95% confidence interval, 1.5-30.6; MLH1: P = 0.04; odds ratio, 25.4; 95% confidence interval, 1.2-143; SMARCE1: P = 0.001; odds ratio, 2047; 95% confidence interval, 52-4.5e15, respectively). CONCLUSIONS: The study provided moderate evidence of gene and disease association of germline mutations in PALB2 and MLH1 with hereditary predisposition to UM. It also identified several other candidate susceptibility genes. The results suggest locus heterogeneity in predisposition to UM. Genetic testing for hereditary predisposition to cancer is warranted in UM patients with strong personal or family history of cancers, or both.


Assuntos
Genes Neoplásicos/genética , Predisposição Genética para Doença/genética , Melanoma/genética , Proteínas de Neoplasias/genética , Neoplasias Uveais/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , DNA de Neoplasias/genética , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Imuno-Histoquímica , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Sequenciamento do Exoma
2.
Invest Ophthalmol Vis Sci ; 60(7): 2474-2480, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31173078

RESUMO

Purpose: The activation of the mitogen-activated protein kinase (MAPK) pathway has been suggested as the major downstream target when GNAQ and GNA11 (GNAQ/11) are mutated in uveal melanoma (UM). However, clinical trials with single agent MEK inhibitor showed no clinical significance in altering the overall outcome of the disease in UM; therefore, we investigated the correlation between naturally occurring mutations in GNAQ/11 and activation of MAPK pathway in vivo in primary UM. Methods: Screening for activating mutations in codons 183 and 209 of GNAQ/11 was carried out by sequencing and restriction fragment length polymorphism (RFLP) in a cohort of 42 primary UM. Activation of the MAPK pathway and other potential downstream signals was assessed by immunohistochemistry and/or Western blot analysis. Potential downstream signaling of mutant and wild type GNAQ/11 was studied by transient transfection assay in nonmutant cell lines. Results: Somatic mutations in GNAQ/11 were observed in 35/42 (83.3%) of primary UM. Tumors with GNAQ/11 mutations showed variations in the activation of ERK1/2 with significant tumor heterogeneity. Weak and undetectable ERK1/2 activation was observed in 4/35 (11.4%) and 8/35 (22.9%) of the GNAQ/11 mutant UM, respectively. Tumor heterogeneity of GNAQ/11 mutations was also observed in a subset of tumors. Conclusions: Our results indicate that there is marked variation in MAPK activation in UM with GNAQ/11 mutations. Thus, GNAQ/11 mutational status is not a sufficient biomarker to adequately predict UM patient responses to single-agent selective MEK inhibitor therapy.


Assuntos
Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Melanoma/enzimologia , Melanoma/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mutação , Neoplasias Uveais/enzimologia , Neoplasias Uveais/genética , Western Blotting , Linhagem Celular Tumoral , Estudos de Coortes , Análise Mutacional de DNA , Humanos , Imuno-Histoquímica , Plasmídeos , Polimorfismo de Fragmento de Restrição , Análise de Sequência de DNA , Transdução de Sinais , Transfecção
3.
Genes Chromosomes Cancer ; 58(9): 650-656, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30883995

RESUMO

Uveal melanoma (UM) is the most common phenotype in patients with germline BAP1 mutation. This study aimed to identify selection criteria for BAP1 germline testing and assessed the role of large deletion/duplication and epigenetic inactivation. One hundred seventy-two UM patients with high risk of hereditary cancer were included. Germline variants in BAP1 were assessed by direct sequencing and large deletion/duplication by multiplex ligation-dependent probe amplification. BAP1 expression in unaffected choroid tissue from a patient with UM was assessed by quantitative RT-PCR and methylation by pyrosequencing. Twenty-eight patients had one or more germline sequence variants in BAP1; seven of these were pathogenic. One hundred forty patients were assessed for large deletion/duplication and in one BAP1 whole gene deletion was detected. In total, eight patients (4.7%) had pathogenic alterations in BAP1 with the highest frequencies of in patients with a personal/family history of ≥2 BAP1-related cancers 6/16 (38%), age of onset <35 years 4/21 (19%) and familial UM 6/34 (18%). One of 19 non-tumor choroid tissues tested showed uncharacteristically low expression as compared to the controls decrease in BAP1 RNA expression but no evidence of constitutional promotor hypermethylation was detected. UM patients with a strong personal or family history of cancers associated with BAP1, early age of onset and familial UM should be assessed for germline variants in BAP1, including large deletions.


Assuntos
Corioide/metabolismo , Deleção de Genes , Mutação em Linhagem Germinativa , Melanoma/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uveais/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Melanoma/metabolismo , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo , Neoplasias Uveais/metabolismo
4.
Genes Chromosomes Cancer ; 56(2): 168-174, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27718540

RESUMO

Uveal melanoma (UM) is the most commonly diagnosed primary intraocular tumor in adults. Familial UM (FUM), defined as two or more family members diagnosed with UM, is rare and estimated at less than 1% of all UM. Currently, BAP1 is the only gene known to contribute significant risk for UM. In this study we aimed to estimate the frequency of BAP1 mutation in FUM and to characterize the family and personal histories of other cancers in these families. We identified 32 families with FUM, including seven families previously reported by our group. BAP1 mutation testing was carried out by direct sequencing of the coding exons and the adjacent untranslated regions of the gene. Germline deletion and duplication analysis of BAP1 was assessed by multiplex ligation-dependent probe amplification (MLPA). Germline BAP1 mutations were found in 6/32 (19%) families. No deletions or duplications were identified in any of the 24 samples tested by MLPA. Combined with published studies, the frequency of BAP1 mutations was 14/64 (22%) in FUM. FUM families without BAP1 mutations have distinct family histories with high rates of prostate cancer in first- and second-degree relatives. It is likely that additional genes conferring risk for FUM exist. It is important to understand key shared features of FUM to focus future research on identifying these additional tumor predisposition syndromes. Though BAP1 should be tested first in these families, FUM families without BAP1 mutation should be explored for additional predisposition genes. © 2016 Wiley Periodicals, Inc.


Assuntos
Biomarcadores Tumorais/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Melanoma/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uveais/genética , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Linhagem , Prognóstico , Neoplasias Uveais/patologia , Adulto Jovem
5.
J Med Genet ; 48(12): 856-9, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21941004

RESUMO

OBJECTIVE: To investigate the potential contribution of germline sequence alterations in the BAP1 gene in uveal melanoma (UM) patients with possible predisposition to hereditary cancer. DESIGN: A total of 53 unrelated UM patients with high risk for hereditary cancer and five additional family members of one proband were studied. Mutational screening was carried out by direct sequencing. RESULTS: Of the 53 UM patients studied, a single patient was identified with a germline BAP1 truncating mutation, c. 799 C→T (p.Q267X), which segregated in several family members and was associated with UM and other cancers. Biallelic inactivation of BAP1 and decreased BAP1 expression were identified in the UM, lung adenocarcinoma and meningioma tumours from three family members with this germline BAP1 mutation. Germline BAP1 variants of uncertain significance, likely non-pathogenic, were also identified in two additional UM patients. CONCLUSION: This study reports a novel hereditary cancer syndrome caused by a germline BAP1 mutation that predisposes patients to UM, lung carcinoma, meningioma, and possibly other cancers. The results indicate that BAP1 is the candidate gene in only a small subset of hereditary UM, suggesting the contribution of other candidate genes.


Assuntos
Adenocarcinoma/genética , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa , Neoplasias Pulmonares/genética , Melanoma/genética , Meningioma/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uveais/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Adulto , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 3/metabolismo , Análise Mutacional de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/metabolismo , Doenças Genéticas Inatas/patologia , Testes Genéticos , Humanos , Perda de Heterozigosidade , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Melanoma/metabolismo , Melanoma/patologia , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/metabolismo , Neoplasias Meníngeas/patologia , Meningioma/metabolismo , Meningioma/patologia , Repetições de Microssatélites , Pessoa de Meia-Idade , Linhagem , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo , Neoplasias Uveais/metabolismo , Neoplasias Uveais/patologia
6.
Invest Ophthalmol Vis Sci ; 51(7): 3333-9, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20164465

RESUMO

PURPOSE. The purposes of this study were to investigate the frequency of MET activation in uveal melanomas (UMs), to study the potential molecular mechanism for its activation, and to assess the utility of MET inhibition as a potential therapy for UM. METHODS. The frequency of MET activation in UMs was studied by using immunohistochemistry and Western blot analysis in 46 primary UMs and six UM cell lines. Sequencing was used for detection of activating mutations in the MET gene, and the effect of selective MET inhibition was assessed by cell proliferation and migration assays. RESULTS. The results showed that the majority (82.5%) of the 46 UMs expressed activated MET protein. Three of the UM cell lines, C918, 92.1, and MEL202, showed strong MET and pMET expression, whereas the other three showed weaker expression. Sequence analysis identified no activating mutations in MET in any of the 22 tumors or in the six UM cell lines. Selective MET blocking showed inhibition of tumor cell proliferation at an IC(50) ranging from 2.5 to 5.2 microM. A significant inhibition of UM cell migration was also observed starting at 1.25 microM. CONCLUSIONS. The results indicate that MET is activated in a significant number of UMs and also that MET activation in UMs is most likely through indirect gene activation rather than copy number alteration or mutation involving the MET gene. MET inhibition could be a target of therapy for UM.


Assuntos
Indóis/farmacologia , Melanoma/terapia , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento/antagonistas & inibidores , Sulfonamidas/farmacologia , Neoplasias Uveais/terapia , Western Blotting , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , DNA de Neoplasias/análise , Humanos , Imuno-Histoquímica , Melanoma/metabolismo , Melanoma/patologia , Fosforilação , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , RNA Mensageiro/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Fatores de Crescimento/genética , Receptores de Fatores de Crescimento/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ativação Transcricional , Neoplasias Uveais/metabolismo , Neoplasias Uveais/patologia
7.
J Clin Endocrinol Metab ; 88(10): 4911-6, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14557473

RESUMO

Approximately 75% of pheochromocytomas are sporadic. Germline mutations in RET, VHL, SDHB, and SDHD have been shown to cause the 25% that are hereditary. Germline high penetrance gain-of-function RET mutations cause multiple endocrine neoplasia type 2, of which medullary thyroid carcinoma (MTC) and pheochromocytoma are components, whereas loss-of-function mutations cause Hirschprung disease (HSCR). A low-penetrance founder locus, in linkage disequilibrium with a RET ancestral haplotype comprising specific alleles at three intron (IVS) 1 single nucleotide polymorphisms (SNPs) (haplotype 0) and SNP A45A, predisposes to the majority of isolated HSCR. A different low-penetrance locus, in linkage disequilibrium with IVS 1 haplotype 2 and SNP S836S, was associated with a subset of sporadic MTC. We, therefore, sought to determine whether RET might also be a low-penetrance gene for apparently sporadic pheochromocytoma. We analyzed 104 pheochromocytoma cases without germline mutations in RET, VHL, SDHD, and SDHB for their status at A45, S836, three IVS 1 SNPs, and a novel upstream insertion/deletion variant. Pheochromocytoma cases were not associated with either A45A or S836S, but we found that cases were associated with haplotype 0 (P = 0.032). However, unlike HSCR, this pheochromocytoma-associated haplotype 0 was not associated with A45A. Taken together with the strengthening of association with the addition of the 5' insertion/deletion variant data (P = 0.016), our observations suggest the presence of a low-penetrance pheochromocytoma susceptibility locus in a region upstream of the putative loci for HSCR and apparently sporadic MTC.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Proteínas Oncogênicas/genética , Feocromocitoma/genética , Polimorfismo de Nucleotídeo Único , Receptores Proteína Tirosina Quinases/genética , Adulto , Idade de Início , Carcinoma Medular/genética , Predisposição Genética para Doença , Haplótipos , Doença de Hirschsprung/genética , Humanos , Íntrons/genética , Desequilíbrio de Ligação , Pessoa de Meia-Idade , Penetrância , Proteínas Proto-Oncogênicas c-ret , Neoplasias da Glândula Tireoide/genética
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