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1.
Genes Chromosomes Cancer ; 52(5): 480-94, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23341105

RESUMO

PALB2/FANCN is a BRCA1- and BRCA2-interacting Fanconi Anemia (FA) protein crucial for key BRCA2 genome caretaker functions. Heterozygous germline mutations in PALB2 predispose to breast cancer and biallelic mutations cause FA. FA proteins play a critical role in the telomere maintenance pathway, with telomeric shortening observed in FA cells. Less is known about telomere maintenance in the heterozygous state. Here, we investigate the roles of PALB2 heterozygous mutations in genomic instability, an important carcinogenesis precursor. Patient-derived lymphoblastoid (LCL) and fibroblast (FCL) cell lines with monoallelic truncating PALB2 mutations were investigated using a combination of molecular imaging techniques including centromeric FISH, telomeric Q-FISH and spectral karyotyping (SKY). Mitomycin C and Cisplatin sensitivity was assayed via cellular metabolism of WST-1. The PALB2 c.229delT FCL showed increases in telomere counts associated with increased mean intensity compared with two wild-type FCLs generated from first-degree relatives (P =1.04E-10 and P =9.68E-15) and it showed evidence of chromosomal rearrangements. Significant differences in centromere distribution were observed in one of three PALB2 heterozygous FCLs analyzed when compared with PALB2 wild-type, BRCA1 and BRCA2 heterozygous FCLs. No significant consistently increased sensitivity to Mitomycin C or Cisplatin was observed in LCLs. Our results are suggestive of an altered centromere distribution profile and a telomere instability phenotype. Together, these may indicate critical nuclear organization defects associated with the predisposition to transformation and early stage development of PALB2-related cancers.


Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Carcinoma Intraductal não Infiltrante/genética , Núcleo Celular/metabolismo , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Proteínas Nucleares/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Estudos de Casos e Controles , Sobrevivência Celular/efeitos dos fármacos , Centrômero/metabolismo , Cisplatino/farmacologia , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Síndrome Hereditária de Câncer de Mama e Ovário/patologia , Heterozigoto , Humanos , Cariótipo , Masculino , Pessoa de Meia-Idade , Mitomicina/farmacologia , Telômero/metabolismo , Células Tumorais Cultivadas
2.
BMC Med Genet ; 14: 5, 2013 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-23302520

RESUMO

BACKGROUND: The PALB2 c.2323C>T [p.Q775X] mutation has been reported in at least three breast cancer families and breast cancer cases of French Canadian descent and this has been attributed to common ancestors. The number of mutation-positive cases reported varied based on criteria of ascertainment of index cases tested. Although inherited PALB2 mutations are associated with increased risks of developing breast cancer, risk to ovarian cancer has not been fully explored in this demographically unique population. METHODS: We screened the PALB2 p.Q775X variant in 71 families with at least three cases of breast cancer (n=48) or breast and ovarian cancers (n=23) that have previously been found negative for at least the most common BRCA1 and BRCA2 mutations reported in the French Canadian population and in 491 women of French Canadian descent who had invasive ovarian cancer and/or low malignant potential tumors of the major histopathological subtypes. RESULTS: We identified a PALB2 p.Q775X carrier in a breast cancer family, who had invasive ductal breast carcinomas at 39 and 42 years of age. We also identified a PALB2 p.Q775X carrier who had papillary serous ovarian cystadenocarcinoma at age 58 among the 238 serous subtype ovarian cancer cases investigated, who also had breast cancer at age 52. CONCLUSION: Our findings, taken together with previous reports, support adding PALB2 c.2323C>T p.Q775X to the list of cancer susceptibility genes for which founder mutations have been identified in the French Canadian population.


Assuntos
Neoplasias da Mama/genética , Efeito Fundador , Mutação em Linhagem Germinativa , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Proteínas Supressoras de Tumor/genética , População Branca/genética , Adulto , Idoso , Sequência de Bases , Canadá/etnologia , Família , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Heterozigoto , Humanos , Pessoa de Meia-Idade , Linhagem
3.
J Med Genet ; 47(12): 863-6, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21036787

RESUMO

BACKGROUND: Multilocular cystic nephroma (CN) is a benign kidney tumour and is part of a family of kidney neoplasms including cystic partially differentiated nephroblastoma and Wilms tumour (WT). CN is rarely familial or bilateral, but it occurs in about 10% of families where pleuropulmonary blastoma (PPB) is present. Recently, germline mutations in DICER1 were found in familial PPB. OBJECTIVE: To search for DICER1 mutations in two families with familial CN; PPB was present in one family. Additionally, to test germline DNA from 50 children with sporadic WT for DICER1 mutations. RESULTS: Both families with multiple CN were found to have mutations in DICER1 leading to premature stop codons, predicted to result in loss of the ribonuclease and dsRNA binding domains. These domains are essential to the function of DICER1. No germline mutations were found in any of the 50 children who had developed WT. CONCLUSION: It has been established that DICER1 mutations cause familial CN and may be implicated in bilateral CN. No germline mutations were found in the patients with WT, suggesting that DICER1 mutations are unlikely to have a major role in the aetiology of sporadic WT. These results provide further evidence implicating miRNA dysregulation in tumourigenesis.


Assuntos
RNA Helicases DEAD-box/genética , Mutação em Linhagem Germinativa/genética , Doenças Renais Císticas/complicações , Doenças Renais Císticas/genética , Neoplasias Renais/complicações , Neoplasias Renais/genética , Ribonuclease III/genética , Adolescente , Adulto , Sequência de Bases , Criança , Pré-Escolar , Análise Mutacional de DNA , Família , Feminino , Humanos , Lactente , Doenças Renais Císticas/patologia , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Adulto Jovem
4.
JAMA ; 305(1): 68-77, 2011 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-21205968

RESUMO

CONTEXT: Nontoxic multinodular goiter (MNG) is frequently observed in the general population, but little is known about the underlying genetic susceptibility to this disease. Familial cases of MNG have been reported, and published reports describe 5 families that also contain at least 1 individual with a Sertoli-Leydig cell tumor of the ovary (SLCT). Germline mutations in DICER1, a gene that codes for an RNase III endoribonuclease, have been identified in families affected by pleuropulmonary blastoma (PPB), some of whom include cases of MNG and gonadal tumors such as SLCTs. OBJECTIVE: To determine whether familial MNG with or without SLCT in the absence of PPB was associated with mutations in DICER1. DESIGN, SETTING, AND PATIENTS: From September 2009 to September 2010, we screened 53 individuals from 2 MNG and 3 MNG/SLCT families at McGill University for mutations in DICER1. We investigated blood lymphocytes and MNG and SLCT tissue from family members for loss of the wild-type DICER1 allele (loss of heterozygosity), DICER1 expression, and microRNA (miRNA) dysregulation. MAIN OUTCOME MEASURE: Detection of germline DICER1 gene mutations in familial MNG with and without SLCT. RESULTS: We identified and characterized germline DICER1 mutations in 37 individuals from 5 families. Two mutations were predicted to be protein truncating, 2 resulted in in-frame deletions, and 1 was a missense mutation. Molecular analysis of the 3 SLCTs showed no loss of heterozygosity of DICER1, and immunohistochemical analysis in 2 samples showed strong expression of DICER1 in Sertoli cells but weak staining of Leydig cells. miRNA profiling of RNA from lymphoblastoid cell lines from both affected and unaffected members of the familial MNG cases revealed miRNA perturbations in DICER1 mutation carriers. CONCLUSIONS: DICER1 mutations are associated with both familial MNG and MNG with SLCT, independent of PPB. These germline DICER1 mutations are associated with dysregulation of miRNA expression patterns.


Assuntos
RNA Helicases DEAD-box/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Bócio Nodular/genética , Neoplasias Ovarianas/genética , Ribonuclease III/genética , Adolescente , Adulto , Criança , Análise Mutacional de DNA , Feminino , Bócio Nodular/complicações , Humanos , Masculino , MicroRNAs/metabolismo , Mutação de Sentido Incorreto , Neoplasias Ovarianas/complicações , Blastoma Pulmonar/complicações , Blastoma Pulmonar/genética , Tumor de Células de Sertoli-Leydig/complicações , Tumor de Células de Sertoli-Leydig/genética , Adulto Jovem
5.
J Hum Genet ; 55(12): 842-3, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20844547

RESUMO

MRG15 is a recently identified member of the BRCA multiprotein complex, essential for the maintenance of the genome integrity and DNA repair. The functional relationship between PALB2 and MRG15 makes MRG15 a strong candidate breast cancer susceptibility gene. We screened affected probands from 232 BRCA1/2-negative breast cancer families for mutations in MRG15. We identified seven previously unreported variants but in silico analyses revealed that none of these variants appears to modify the function of MRG15. Thus, it seems unlikely that any constitutional changes in MRG15 confer an increased risk for breast cancer.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Proteínas Nucleares/metabolismo , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/epidemiologia , Análise Mutacional de DNA , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Pessoa de Meia-Idade , Risco , Fatores de Transcrição/metabolismo , Adulto Jovem
6.
Fam Cancer ; 10(4): 659-65, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21779980

RESUMO

This is an 11-year survey of molecular analysis of APC germline mutations for the province of Quebec done at the Molecular Pathology Unit of the Jewish General Hospital which offers genetic testing for hereditary forms of colorectal cancer for the whole of Quebec province. We report on 47 unique mutations seen in 66 families affected with familial adenomatous polyposis. Of these unique mutations, 60% are short indels, 28% are point mutations, and 6% are whole exon deletions. The absence of founder mutations and the variety of mutations encountered reinforce the value of RNA-based testing and the need for gene dosage techniques such as multiplex ligation-dependent probe amplification.


Assuntos
Polipose Adenomatosa do Colo/genética , Análise Mutacional de DNA , Genes APC , Mutação em Linhagem Germinativa , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Éxons , Feminino , Testes Genéticos/métodos , Humanos , Lactente , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutagênese Insercional , Mutação Puntual , Quebeque , Análise de Sequência de DNA , Deleção de Sequência
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