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1.
Clin Epigenetics ; 11(1): 171, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31779681

RESUMO

Constitutional MLH1 methylation (epimutation) is a rare cause of Lynch syndrome. Low-level methylation (≤ 10%) has occasionally been described. This study aimed to identify low-level constitutional MLH1 epimutations and determine its causal role in patients with MLH1-hypermethylated colorectal cancer.Eighteen patients with MLH1-hypermethylated colorectal tumors in whom MLH1 methylation was previously undetected in blood by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) were screened for MLH1 methylation using highly sensitive MS-melting curve analysis (MS-MCA). Constitutional methylation was characterized by different approaches.MS-MCA identified one patient (5.6%) with low-level MLH1 methylation (~ 1%) in blood and other normal tissues, which was confirmed by clonal bisulfite sequencing in blood. The patient had developed three clonally related gastrointestinal MLH1-methylated tumor lesions at 22, 24, and 25 years of age. The methylated region in normal tissues overlapped with that reported for other carriers of constitutional MLH1 epimutations. Low-level MLH1 methylation and reduced allelic expression were linked to the same genetic haplotype, whereas the opposite allele was lost in patient's tumors. Mutation screening of MLH1 and other hereditary cancer genes was negative.Herein, a highly sensitive MS-MCA-based approach has demonstrated its utility for the identification of low-level constitutional MLH1 epigenetic mosaicism. The eventual identification and characterization of additional cases will be critical to ascertain the cancer risks associated with constitutional MLH1 epigenetic mosaicism.

2.
Hum Mutat ; 40(9): 1557-1578, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31131967

RESUMO

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.

4.
Med. clín (Ed. impr.) ; 146(4): 148-154, feb. 2016. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-147837

RESUMO

Fundamento y objetivo: Tener una predisposición hereditaria al cáncer puede asociarse a un impacto psicológico. Uno de los objetivos del consejo genético es favorecer la adaptación psicológica a la nueva situación, siendo necesarios instrumentos validados en este contexto. Por ser el autoconcepto un buen indicador de adaptación a la enfermedad o al riesgo de tenerla, y una variable relevante en oncología, el objetivo es adaptar culturalmente al castellano y validar la BRCA Self-Concept Scale. Material y método: Ciento sesenta y cinco portadoras de mutación en los genes BRCA respondieron al cuestionario previamente sometido a un proceso de traducción-retrotraducción, y a la Escala de Preocupación por el Cáncer (EPC) como medida de validez convergente. Se valoró la estructura del cuestionario mediante una prueba de expertos y un análisis factorial confirmatorio (AFC), se calculó el α de Cronbach de las 3 subescalas (Estigma, Vulnerabilidad y Control), y se correlacionaron con la EPC. Resultados: La prueba de expertos y el AFC no confirman la estructura original del cuestionario. El modelo reespecificado (con los ítems 10 y 13 en Vulnerabilidad) muestra mejor ajuste: comparative fit index 0,973;Tucker-Lewis index 0,968; root mean square error of approximation 0,067. El α de Cronbach es de 0,83 para Estigma, de 0,84 para Vulnerabilidad, y de 0,61 para Control. Se encuentra evidencia de validez convergente con la EPC (rho de Spearman 0,631 para Estigma, 0,683 para Vulnerabilidad, y −0,363 para Control; p < 0,001). Conclusiones: Los resultados apoyan la validez de la escala modificada de autoconcepto BRCA, siendo una medida potencialmente útil para valorar la adaptación a tener una alta predisposición hereditaria al cáncer (AU)


Background and objective: Having an inherited predisposition to cancer may have a psychological impact, and one goal of genetic counseling is to promote psychological adjustment to the new situation. Thus, in the genetic context, validated measures of adjustment are required. Given that self-concept is a good indicator of adjustment to the disease or to the risk for it, and a relevant variable in oncology, the goal of the study is to culturally adapt and validate the BRCA Self-Concept Scale. Material and Method: One hundred and sixty-five BRCA carriers’ women answered to the questionnaire, previously adapted through a process of forward/back-translation, and to the Cancer Worry Scale (CWS) as a measure of convergent validity. Theoretical structure of BRCA Self-Concept Scale was assessed by expert judges, and submitted to a confirmatory factor analysis (CFA). Cronbach's α was calculated for each subscale (Stigma, Vulnerability and Control), and correlations with CWS were performed. Results: Expert judges’ structure and CFA do not support the original structure of the questionnaire. The respecificity model (with items 10 and 13 loading on Vulnerability factor) show a better fit: comparative fit index 0.973; Tucker-Lewis index 0.968; root mean square error of approximation 0.067. The Cronbach's α is 0.83 for Stigma, 0.84 for Vulnerability, and 0.61 for Control. Evidence of convergent validity with CWS has been obtained (Spearman's rho 0.631 for Stigma, 0.683 for Vulnerability, and −0.363 for Control; P < .001). Conclusions: Results support the validity of the modified Spanish BRCA Self-Concept Scale, which is a potentially useful measure for the study of psychological adjustment to high risk for hereditary breast and ovarian cáncer (AU)


Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Ajustamento Social , Autoimagem , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/psicologia , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/psicologia , Mutagênese/genética , Adaptação Psicológica/fisiologia , Imagem Corporal , Inquéritos e Questionários , Adaptação Psicológica/classificação , Psicometria/métodos , Psicometria/tendências
5.
Genet Med ; 18(4): 325-32, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26133394

RESUMO

PURPOSE: Germ-line mutations in the exonuclease domains of POLE and POLD1 have been recently associated with polyposis and colorectal cancer (CRC) predisposition. Here, we aimed to gain a better understanding of the phenotypic characteristics of this syndrome to establish specific criteria for POLE and POLD1 mutation screening and to help define the clinical management of mutation carriers. METHODS: The exonuclease domains of POLE and POLD1 were studied in 529 kindred, 441 with familial nonpolyposis CRC and 88 with polyposis, by using pooled DNA amplification and massively parallel sequencing. RESULTS: Seven novel or rare genetic variants were identified. In addition to the POLE p.L424V recurrent mutation in a patient with polyposis, CRC and oligodendroglioma, six novel or rare POLD1 variants (four of them, p.D316H, p.D316G, p.R409W, and p.L474P, with strong evidence for pathogenicity) were identified in nonpolyposis CRC families. Phenotypic data from these and previously reported POLE/POLD1 carriers point to an associated phenotype characterized by attenuated or oligo-adenomatous colorectal polyposis, CRC, and probably brain tumors. In addition, POLD1 mutations predispose to endometrial and breast tumors. CONCLUSION: Our results widen the phenotypic spectrum of the POLE/POLD1-associated syndrome and identify novel pathogenic variants. We propose guidelines for genetic testing and surveillance recommendations.Genet Med 18 4, 325-332.


Assuntos
Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/genética , DNA Polimerase III/genética , DNA Polimerase II/genética , Mutação , Polipose Adenomatosa do Colo/diagnóstico , Alelos , Neoplasias Colorretais/diagnóstico , DNA Polimerase II/química , DNA Polimerase III/química , Feminino , Estudos de Associação Genética , Testes Genéticos , Genótipo , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Linhagem , Fenótipo , Proteínas de Ligação a Poli-ADP-Ribose , Domínios e Motivos de Interação entre Proteínas/genética
6.
Med Clin (Barc) ; 146(4): 148-54, 2016 Feb 19.
Artigo em Espanhol | MEDLINE | ID: mdl-26654557

RESUMO

BACKGROUND AND OBJECTIVE: Having an inherited predisposition to cancer may have a psychological impact, and one goal of genetic counseling is to promote psychological adjustment to the new situation. Thus, in the genetic context, validated measures of adjustment are required. Given that self-concept is a good indicator of adjustment to the disease or to the risk for it, and a relevant variable in oncology, the goal of the study is to culturally adapt and validate the BRCA Self-Concept Scale. MATERIAL AND METHOD: One hundred and sixty-five BRCA carriers' women answered to the questionnaire, previously adapted through a process of forward/back-translation, and to the Cancer Worry Scale (CWS) as a measure of convergent validity. Theoretical structure of BRCA Self-Concept Scale was assessed by expert judges, and submitted to a confirmatory factor analysis (CFA). Cronbach's α was calculated for each subscale (Stigma, Vulnerability and Control), and correlations with CWS were performed. RESULTS: Expert judges' structure and CFA do not support the original structure of the questionnaire. The respecificity model (with items 10 and 13 loading on Vulnerability factor) show a better fit: comparative fit index 0.973; Tucker-Lewis index 0.968; root mean square error of approximation 0.067. The Cronbach's α is 0.83 for Stigma, 0.84 for Vulnerability, and 0.61 for Control. Evidence of convergent validity with CWS has been obtained (Spearman's rho 0.631 for Stigma, 0.683 for Vulnerability, and -0.363 for Control; P<.001). CONCLUSIONS: Results support the validity of the modified Spanish BRCA Self-Concept Scale, which is a potentially useful measure for the study of psychological adjustment to high risk for hereditary breast and ovarian cancer.


Assuntos
Ajustamento Emocional , Síndrome Hereditária de Câncer de Mama e Ovário/psicologia , Testes Psicológicos , Autoimagem , Adulto , Assistência à Saúde Culturalmente Competente , Análise Fatorial , Feminino , Humanos , Pessoa de Meia-Idade , Psicometria , Reprodutibilidade dos Testes , Traduções
7.
Breast ; 21(6): 755-60, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22381151

RESUMO

Genetic testing for breast cancer predisposition has been available in the clinical practice for more than a decade. How the result of genetic testing affects the psychological well-being of the individuals is an under-researched area in many populations. Follow-up analysis of psychological well-being via HADS scale was performed in 364 individuals at 3 months and 1 year after the disclosure of BRCA1/2 genetic result. We analyzed potential predictors for pathological anxiety and variables associated to the variation of HADS scores over time. At pre-test only 16% and 4% of individuals presented symptoms of anxiety and depression, respectively. Having a prior diagnosis of cancer and presenting a pathological HADS-A score at the baseline were associated with clinically significant anxiety scores at one year, but the genetic test result was not. Thus, BRCA genetic testing does not influence short and long term anxiety and depression levels among those identified as mutation carriers. It is our task to demystify the allegedly negative impact of BRCA testing on psychological well being to increase the uptake of genetic testing and benefit those who are at high risk of developing breast, ovarian and prostate cancer.


Assuntos
Ansiedade/etiologia , Depressão/etiologia , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença/psicologia , Testes Genéticos , Síndrome Hereditária de Câncer de Mama e Ovário/psicologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Marcadores Genéticos , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Testes Psicológicos , Fatores de Risco , Espanha , Inquéritos e Questionários , Fatores de Tempo , Adulto Jovem
8.
BMC Cancer ; 12: 84, 2012 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-22401137

RESUMO

BACKGROUND: Genes that, when mutated, cause Fanconi anemia or greatly increase breast cancer risk encode for proteins that converge on a homology-directed DNA damage repair process. Mutations in the SLX4 gene, which encodes for a scaffold protein involved in the repair of interstrand cross-links, have recently been identified in unclassified Fanconi anemia patients. A mutation analysis of SLX4 in German or Byelorussian familial cases of breast cancer without detected mutations in BRCA1 or BRCA2 has been completed, with globally negative results. METHODS: The genomic region of SLX4, comprising all exons and exon-intron boundaries, was sequenced in 94 Spanish familial breast cancer cases that match a criterion indicating the potential presence of a highly-penetrant germline mutation, following exclusion of BRCA1 or BRCA2 mutations. RESULTS: This mutational analysis revealed extensive genetic variation of SLX4, with 21 novel single nucleotide variants; however, none could be linked to a clear alteration of the protein function. Nonetheless, genotyping 10 variants (nine novel, all missense amino acid changes) in a set of controls (138 women and 146 men) did not detect seven of them. CONCLUSIONS: Overall, while the results of this study do not identify clearly pathogenic mutations of SLX4 contributing to breast cancer risk, further genetic analysis, combined with functional assays of the identified rare variants, may be warranted to conclusively assess the potential link with the disease.


Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Mutação de Sentido Incorreto/genética , Recombinases/genética , Análise Mutacional de DNA , Éxons/genética , Família , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Humanos , Íntrons/genética , Masculino
9.
Breast Cancer Res Treat ; 130(1): 341-4, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21761158

RESUMO

In this study, we present a novel complex rearrangement in the BRCA1 gene. The genomic rearrangement was identified using one of the two commercially available MLPA BRCA1 kits but was not confirmed with the other. In this report, we present the full characterization at the DNA and RNA levels of a new partial deletion of exon 20 of BRCA1. This is a complex deletion with four breakpoints which promotes aberrant splicing with partial deletion of exon 20 plus the insertion of a cryptic exon corresponding to a fragment of intron 20. The aberrant splicing generates an abnormal transcript with a frameshift that will result in a truncated BRCA1 protein.


Assuntos
Éxons , Genes BRCA1 , Neoplasias Ovarianas/genética , Deleção de Sequência , Adulto , Sequência de Bases , Feminino , Ordem dos Genes , Humanos , Dados de Sequência Molecular , Linhagem , Processamento de RNA , Alinhamento de Sequência
10.
Fam Cancer ; 9(3): 297-304, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20091130

RESUMO

Identifying a BRCA mutation among families with hereditary breast and ovarian cancer enables distinguishing those who may benefit from a specific medical management. This study aimed to evaluate the uptake of predictive testing among close relatives of a proband in Spanish families with a BRCA1 or BRCA2 mutation, and to determine the associated demographic and clinical predictors. A retrospective cohort of families undergoing clinical genetic testing at four university hospitals in northeastern Spain was considered. From 108 unrelated BRCA1/2 families, 765 close relatives of probands were analyzed. Sixty percent of the first-degree and 28% of the second-degree relatives underwent predictive testing within a median time of 2 and 6 months, respectively, since the mutation disclosure to the proband. Relatives undergoing genetic testing were more likely to be female, first-degree, and belong to a family with a proband who had a high educational level. Relatives were also more likely to have offspring, a previous cancer diagnosis, and to be aged between 30 and 64 years. Among second-degree relatives, having a first-degree relative with cancer was highly correlated with uptake. In conclusion, uptake of BRCA1/2 predictive testing among close relatives was notably high and within a short period of time after disclosure of the mutation to the proband. Being female, a high educational level of the proband, and having a close relative with cancer were associated with uptake among relatives. Further studies are warranted to determine whether information is disseminated properly by probands and to learn about the reasons for those not undergoing testing.


Assuntos
Neoplasias da Mama/diagnóstico , Genes BRCA1 , Genes BRCA2 , Testes Genéticos/estatística & dados numéricos , Neoplasias Ovarianas/diagnóstico , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/psicologia , Neoplasias da Mama Masculina/diagnóstico , Neoplasias da Mama Masculina/genética , Neoplasias da Mama Masculina/psicologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/psicologia , Linhagem , Estudos Retrospectivos , Fatores Socioeconômicos , Espanha
11.
Breast Cancer Res Treat ; 122(3): 733-43, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19894111

RESUMO

Large genomic rearrangements are estimated to account for approximately 5-10% of all disease-causing mutations in BRCA1 and BRCA2 genes in patients with hereditary breast and ovarian cancer syndrome (HBOC). We use MRC-Holland Multiplex Ligation-dependent Probe Amplification (MLPA) to screen for such rearrangements in patients with HBOC and as a first step in our genetic testing workflow. The technique was applied to a set of 310 independent patients and detected eight different copy number alterations, corresponding to 2.6% of the studied samples. MLPA was also found to identify point mutations located in probe sequences. As commercial MLPA tests are not suitable for determining the specific breakpoints or for defining the exact extent of rearrangements, we applied a set of different complementary techniques to characterize these genetic alterations with greater precision. Long-range PCR amplification, RNA analysis, SNP-array chips, non-commercial MLPA probes, and FISH analysis were used to fully define the extent and mechanism of each alteration. In BRCA1, six rearrangements were characterized: deletion of E22, duplication of E9-E24, deletion of E16-E23, deletion of E1-E13, deletion of E1-E2 and duplication of E1-E2. In BRCA2, we studied a deletion of E15-E16 and a deletion of E1-E24. To the best of our knowledge, this is the most comprehensive study of the nature and underlying molecular causes of these mutational events in the BRCA1/2 genes.


Assuntos
Neoplasias da Mama/genética , Rearranjo Gênico , Genes BRCA1 , Genes BRCA2 , Genoma Humano , Neoplasias Ovarianas/genética , Adulto , Sequência de Bases , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Mutação Puntual , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Homologia de Sequência do Ácido Nucleico
12.
Hum Reprod ; 24(4): 1000-6, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19112076

RESUMO

BACKGROUND: Mutations in breast cancer BRCA1/2 genes increase breast and ovarian cancer risk and are transmitted with an autosomal dominant pattern. Opinion about reproductive decisions among individuals undergoing BRCA1/2 testing in our institutions is unknown. MATERIALS AND METHODS: Individuals (n = 77) undergoing BRCA1/2 testing were included in a prospective multicentre study to assess the clinical impact of genetic testing. Demographic and clinical information, psychological status and opinion about reproductive decisions were collected in two questionnaires administered prior to testing. Opinion regarding the use of assisted reproduction techniques for hereditary cancer susceptibility among health care professionals was also collected. RESULTS: Twenty-eight individuals (36%) reported that they would decide to have children, regardless of their result. In case of a mutation, 9 (12%) believed that they would decide not to have children, 42 (55%) would consider prenatal diagnosis (PND), 37 (48%) would consider preimplantation genetic diagnosis (PGD) and 23 (30%) would consider adoption. Fifty-seven (74%) and 47 (61%) reported that they considered it ethical to offer PND or PGD, respectively, to BRCA+ patients. Individuals older than 40 years were more likely to consider PND or PGD than younger subjects (P = 0.02 and 0.05, respectively). Individuals with cancer compared with those without a diagnosis of malignancy were more likely to consider PGD (61 versus 30%, P = 0.02) and to consider that it was ethical to offer it (74 versus 44%, P = 0.02). Most health care professionals were in favour of PND and PGD for individuals with hereditary cancer susceptibility (58 and 61%, respectively). CONCLUSIONS: BRCA1/2 genetic results could influence an individual's decisions regarding reproduction. Health care professionals who serve individuals undergoing BRCA testing should incorporate patient education regarding the potential impact of such testing on family planning.


Assuntos
Genes BRCA1 , Genes BRCA2 , Testes Genéticos/psicologia , Reprodução , Adulto , Idoso , Idoso de 80 Anos ou mais , Atitude , Neoplasias da Mama/genética , Tomada de Decisões , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/genética , Gravidez , Diagnóstico Pré-Implantação/ética , Diagnóstico Pré-Natal/ética , Estudos Prospectivos , Técnicas de Reprodução Assistida , Espanha , Inquéritos e Questionários , Adulto Jovem
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