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‣ E-Cadherin (CDH1) and p53 rather than SMAD4 and Caspase-10 germline mutations contribute to genetic predisposition in Portuguese gastric cancer patients

Oliveira, Carla; Ferreira, Paulo; Nabais, Sérgio; Campos, Luísa; Ferreira, Ana; Cirnes, Luís; Alves, Catarina Castro; Veiga, Isabel; Fragoso, Maria; Regateiro, Fernando; Dias, Luís Moreira; Moreira, Herculano; Suriano, Gianpaolo; Machado, José Carlos
Fonte: Universidade de Coimbra Publicador: Universidade de Coimbra
Tipo: Artigo de Revista Científica Formato: aplication/PDF
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Approximately 30% of all hereditary diffuse gastric cancer (HDGC) families carry CDH1 germline mutations. The other two thirds remain genetically unexplained and are probably caused by alterations in other genes. Using polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP)/sequencing, we screened 32 Portuguese families with a history of gastric cancer and 23 patients with early onset gastric cancer for CDH1 germline mutations. In probands negative for CDH1 mutations, we screened genes involved in hereditary cancer syndromes in which gastric cancer may be one of the component tumours, namely p53 (Li-Fraumeni Syndrome) and hMLH1 and hMSH2 (HNPCC). We also screened in these patients for mutations in Caspase-10, a gene inactivated in sporadic gastric cancer, and SMAD4, a gene whose inactivation in mice is associated with signet-ring cell carcinoma of the stomach. One of the families fulfilling the HDGC criteria harboured a CDH1 germline mutation, and one of the families with incomplete criteria harboured a p53 germline mutation. No mutations were identified in hMLH1 and hMSH2, and only sequence variants were found in SMAD4 and Caspase-10. The present work reports for the first time CDH1 germline mutations in Portuguese gastric cancer families...

‣ Clinical and molecular characterization of Brazilian families with von Hippel-Lindau disease: a need for delineating genotype-phenotype correlation

GOMY, Israel; MOLFETTA, Greice Andreotti; BARRETO, Ester de Andrade; FERREIRA, Cristiane Ayres; ZANETTE, Dalila Luciola; CASALI-DA-ROCHA, Jose Claudio; SILVA JR., Wilson Araujo
Fonte: SPRINGER Publicador: SPRINGER
Tipo: Artigo de Revista Científica
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von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary cancer syndrome that predisposes to the development of a variety of benign and malignant tumours, especially cerebellar haemangioblastomas, retinal angiomas and clear-cell renal cell carcinomas (RCC). The etiology and manifestations are due to germline and somatic mutations in the VHL tumour suppressor gene. VHL disease is classified into type 1 and type 2, showing a clear genotype-phenotype correlation, as type 2 is associated with phaeochromocytoma and essentially caused by missense mutations. The aim of this study is to characterize the phenotype and genotype of families with VHL disease. Eighteen of twenty patients from ten unrelated families underwent genetic testing, nine of them fulfilled VHL disease criteria and one had an apparently sporadic cerebellar haemangioblastoma. Four different germline mutations in the VHL gene were identified: c.226_228delTTC (p.Phe76del); c.217C > T (p.Gln73X); IVS1-1 G > A and IVS2-1 G > C. The first three mutations were associated with type 1 disease and the last one with type 2B, which had never been identified in the germline. The transcriptional processing of a novel splice-site mutation was characterised. Three type 1 VHL families showed large deletions of the VHL gene...

‣ Predictive models for mutations in mismatch repair genes: implication for genetic counseling in developing countries

Santos, Erika Maria Monteiro; Valentin, Mev Dominguez; Carneiro, Felipe; Oliveira, Ligia Petrolini de; Ferreira, Fabio de Oliveira; Aguiar Junior, Samuel; Nakagawa, Wilson Toshihiko; Gomy, Israel; Ferraz, Victor Evangelista de Faria; Silva Junior, Wilson
Fonte: BIOMED CENTRAL LTD; LONDON Publicador: BIOMED CENTRAL LTD; LONDON
Tipo: Artigo de Revista Científica
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Background: Lynch syndrome (LS) is the most common form of inherited predisposition to colorectal cancer (CRC), accounting for 2-5% of all CRC. LS is an autosomal dominant disease characterized by mutations in the mismatch repair genes mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), postmeiotic segregation increased 1 (PMS1), post-meiotic segregation increased 2 (PMS2) and mutS homolog 6 (MSH6). Mutation risk prediction models can be incorporated into clinical practice, facilitating the decision-making process and identifying individuals for molecular investigation. This is extremely important in countries with limited economic resources. This study aims to evaluate sensitivity and specificity of five predictive models for germline mutations in repair genes in a sample of individuals with suspected Lynch syndrome. Methods: Blood samples from 88 patients were analyzed through sequencing MLH1, MSH2 and MSH6 genes. The probability of detecting a mutation was calculated using the PREMM, Barnetson, MMRpro, Wijnen and Myriad models. To evaluate the sensitivity and specificity of the models, receiver operating characteristic curves were constructed. Results: Of the 88 patients included in this analysis, 31 mutations were identified: 16 were found in the MSH2 gene...

‣ Identificação e caracterização de mutações germinativas no gene VHL em famílias com a doença de von Hippel-Lindau; Identification and characterization of germline mutations in the VHL gene in families with von Hippel-Lindau disease

Gomy, Israel
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 02/07/2008 Português
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A doença de von Hippel-Lindau (VHL) é uma síndrome de câncer familial herdada de forma autossômica dominante que predispõe ao desenvolvimento de diversos tipos de neoplasias benignas e malignas. É causada por mutações germinativas e somáticas no gene VHL e tem uma incidência aproximada de um a cada 36.000 nascimentos. O gene VHL é um supressor tumoral e codifica a proteína VHL, a qual possui, entre outras funções, uma atividade ubiquitina-ligase, responsável pela poliubiquitinização e degradação proteassômica da subunidade alfa do fator induzido por hipóxia (HIF) na presença de oxigênio. As principais características da doença de VHL são: hemangioblastomas de sistema nervoso central (SNC), principalmente do cerebelo e medula espinhal; angiomas de retina e carcinoma renal de células claras. A probabilidade de desenvolver cada um desses tumores ao longo da vida é estimada em maior que 70%, podendo manifestar-se desde a infância até a fase adulta, principalmente entre a 2ª e 3ª décadas de vida. Classifica-se a doença de VHL conforme a ausência (tipo 1) ou presença de feocromocitoma (tipo 2). A doença do tipo 2 é causada, essencialmente, por mutações missense no gene VHL. As mutações podem ser grandes deleções (20%) ou pontuais (80%) do tipo missense...

‣ Investigação de Mutações no Gene BRCA1 em Famílias Brasileiras com Suspeita da Síndrome Hereditária do Câncer de Mama e/ou Ovário.; Investigation of Mutations in the BRCA1 Gene in Brazilian Families with Suspected of Hereditary Breast and Ovarian Cancer Syndrome.

Cury, Nathália Moreno
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 27/04/2012 Português
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Cerca de 10% dos casos de câncer de mama e/ou ovário são caracterizados como hereditários, onde a presença de mutações germinativas no gene de suscetibilidade BRCA1 aumenta o risco de desenvolver esses cânceres durante a vida da mulher. O BRCA1 é um gene supressor tumoral envolvido na resposta de danos ao DNA, controle do ciclo celular, na remodelação da cromatina, ubiquitinação e regulação da transcrição. O presente estudo tem como objetivo central caracterizar as mutações do gene BRCA1 associadas a Síndrome Hereditária do Câncer de Mama e/ou Ovário (HBOC) em pacientes atendidos no Serviço de Aconselhamento Genético do Câncer do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HCFMRP/USP). Os vinte e dois éxons codificantes do BRCA1 foram analisados utilizando o método de High Resolution Melting (HRM) para triagem de mutações pontuais, seguido pelo sequenciamento de DNA dos casos selecionados para validação. A técnica de MLPA (Multiplex Ligation-dependent Probe Amplification) também foi usada para detectar grandes deleções e duplicações. Uma vez confirmada a mutação, membros da família considerados de alto risco, serão investigados para a mutação específica...

‣ Accumulation of p53 protein is frequent in ovarian cancers associated with BRCA1 and BRCA2 germline mutations.

Zweemer, R P; Shaw, P A; Verheijen, R M; Ryan, A; Berchuck, A; Ponder, B A; Risch, H; McLaughlin, J R; Narod, S A; Menko, F H; Kenemans, P; Jacobs, I J
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /05/1999 Português
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BACKGROUND: Mutations in the BRCA1 or BRCA2 genes are responsible for up to 95% of hereditary ovarian cancer cases. Both genes function as tumour suppressor genes, and development of a cancer is thought to require an accumulation of somatic genetic events in addition to the inherited germline predisposition. It is unknown whether these somatic events in BRCA associated ovarian cancer are similar to or distinct from those in sporadic cases. The most frequent somatic genetic event in ovarian cancer is a mutation of the p53 gene. AIM: To study the role of p53 in hereditary ovarian cancer, by analysing accumulation of the p53 protein in ovarian cancers which occurred in BRCA1 or BRCA2 germline mutation carriers and comparing the results with a panel of ovarian cancers from patients who tested negative for both BRCA1 and BRCA2. METHODS: The study group consisted of 39 ovarian cancer patients in whom a BRCA mutation had been confirmed previously. p53 Immunohistochemistry was performed on archival tissue using a standard microwave antigen retrieval technique. The rate of p53 accumulation was compared with 40 ovarian cancer cases who tested negative for BRCA1 and BRCA2 germline mutations. RESULTS: P53 Accumulation was similar in BRCA related ovarian cancers and BRCA negative controls. Overall 27 of 39 BRCA1 or BRCA2 positive cases (69%) had evidence of p53 accumulation...

‣ Germline Mutations in BMPR1A/ALK3 Cause a Subset of Cases of Juvenile Polyposis Syndrome and of Cowden and Bannayan-Riley-Ruvalcaba Syndromes*

Zhou, Xiao-Ping; Woodford-Richens, Kelly; Lehtonen, Rainer; Kurose, Keisuke; Aldred, Micheala; Hampel, Heather; Launonen, Virpi; Virta, Sanno; Pilarski, Robert; Salovaara, Reijo; Bodmer, Walter F.; Conrad, Beth A.; Dunlop, Malcolm; Hodgson, Shirley V.; Iw
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
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Juvenile polyposis syndrome (JPS) is an inherited hamartomatous-polyposis syndrome with a risk for colon cancer. JPS is a clinical diagnosis by exclusion, and, before susceptibility genes were identified, JPS could easily be confused with other inherited hamartoma syndromes, such as Bannayan-Riley-Ruvalcaba syndrome (BRRS) and Cowden syndrome (CS). Germline mutations of MADH4 (SMAD4) have been described in a variable number of probands with JPS. A series of familial and isolated European probands without MADH4 mutations were analyzed for germline mutations in BMPR1A, a member of the transforming growth-factor β–receptor superfamily, upstream from the SMAD pathway. Overall, 10 (38%) probands were found to have germline BMPR1A mutations, 8 of which resulted in truncated receptors and 2 of which resulted in missense alterations (C124R and C376Y). Almost all available component tumors from mutation-positive cases showed loss of heterozygosity (LOH) in the BMPR1A region, whereas those from mutation-negative cases did not. One proband with CS/CS-like phenotype was also found to have a germline BMPR1A missense mutation (A338D). Thus, germline BMPR1A mutations cause a significant proportion of cases of JPS and might define a small subset of cases of CS/BRRS with specific colonic phenotype.

‣ Cryptic von Hippel-Lindau disease: germline mutations in patients with haemangioblastoma only

Hes, F; McKee, S; Taphoorn, M; Rehal, P; van der Luijt, R B; McMahon, R; van der Smagt, J J; Dow, D; Zewald, R; Whittaker, J; Lips, C; MacDonald, F; Pearson, P; Maher, E
Fonte: BMJ Group Publicador: BMJ Group
Tipo: Artigo de Revista Científica
Publicado em /12/2000 Português
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OBJECTIVES— Central nervous system haemangioblastoma (HAB) is a major feature of von Hippel-Lindau (VHL) disease, and it is estimated that about 30% of HAB patients have VHL disease. Consequently, it is widely recommended that sporadic HAB patients are screened for clinical and radiological features of VHL disease because of the risk of multiple tumours. We investigated the frequency of VHL germline mutations in patients with HAB only with no clinical or radiological evidence of VHL disease to define the role of molecular genetic analysis in the management of such patients.
METHODS—Eighty four patients with a single HAB (23 Dutch, 61 UK) and four with multiple HAB (two Dutch, two UK) were studied by direct sequencing of the coding region and quantitative Southern blotting.
RESULTS—A VHL germline mutation was found in three of 69 (4.3%) single HAB patients aged 50 years or less (three of 84 (3.6%) total single HAB patients). A germline VHL mutation was detected in a 44 year old woman with a solitary cerebellar HAB, as well as in four clinically unaffected close relatives, and in two single HAB cases presenting at the ages of 29 and 36 years. Germline VHL mutations were detected in two of four cases with multiple HAB.
CONCLUSIONS—Early detection of VHL disease is important to reduce morbidity and mortality and therefore we recommend that...

‣ Germline Mutations but Not Somatic Changes at the MYH Locus Contribute to the Pathogenesis of Unselected Colorectal Cancers

Halford, Sarah E. R.; Rowan, Andrew J.; Lipton, Lara; Sieber, Oliver M.; Pack, Kevin; Thomas, Huw J. W.; Hodgson, Shirley V.; Bodmer, Walter F.; Tomlinson, Ian P. M.
Fonte: American Society for Investigative Pathology Publicador: American Society for Investigative Pathology
Tipo: Artigo de Revista Científica
Publicado em /05/2003 Português
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MYH-associated polyposis is a recently described, autosomal recessive condition comprising multiple colorectal adenomas and cancer. This disease is caused by germline mutations in the base excision repair (BER) gene MYH. Genes involved in the BER pathway are thus good candidates for involvement in the pathogenesis of sporadic tumors of the large bowel. We have screened a set of 75 sporadic colorectal cancers for mutations in MYH, MTH1, and OGG1. Allelic loss at MYH was also assessed. Selected samples were screened for mutations and allele loss at APC and mutations in p53, K-ras, and β-catenin. A panel of 35 colorectal cancer cell lines was screened for MYH mRNA and protein expression. One of 75 cancers had bi-allelic germline mutations in MYH and on retrospective analysis of medical records this patient was found to have synchronous multiple small adenomas in addition to carcinoma. No somatic MYH mutations were found and mRNA and protein were expressed in all of our cell lines. There were no clearly pathogenic mutations in MTH1 or OGG1 in any tumor. Bi-allelic germline MYH mutations cause ∼1 to 3% of unselected colorectal cancers, but appear always to be associated with multiple adenomas. Somatic inactivation of the DNA glycosylases involved in the BER pathway however does not appear to be involved in colorectal tumorigenesis.

‣ New germline mutations in the hypervariable minisatellite CEB1 in the parents of children with leukaemia

Davies, B G; Hussain, A; Ring, S M; Birch, J M; Eden, T O B; Reeves, M; Dubrova, Y E; Taylor, G M
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
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Gardner and co-workers advanced the hypothesis that the Seascale leukaemia cluster could have been caused by new mutations in germ cells, induced by paternal preconceptional irradiation (PPI) exposure at the Sellafield nuclear installation. Since evidence has shown that PPI can increase the de novo germline mutation rate in hypervariable minisatellite loci, we investigated the hypothesis that sporadic childhood leukaemia might be associated with an increased parental germline minisatellite mutation rate. To test this hypothesis, we compared de novo germline mutation rates in the hypervariable minisatellite locus, CEB1, in family trios (both parents and their child) of children with leukaemia (n=135) compared with unaffected control families (n=124). The majority of case and control germline mutations were paternal (94%); the mean paternal germline mutation rates of children with leukaemia (0.083) and control children (0.156) were not significantly different (odds ratio, 95% confidence interval: 0.50, 0.23–1.08; P=0.11). There were no significant differences in case and control parental allele sizes, case and control germline mutation progenitor allele sizes (2.74 vs 2.54 kb; P=0.56), case and control mutant allele sizes (2.71 vs 2.67 kb; P=0.90)...

‣ MSH6 germline mutations in early-onset colorectal cancer patients without family history of the disease

Pinto, C; Veiga, I; Pinheiro, M; Mesquita, B; Jeronimo, C; Sousa, O; Fragoso, M; Santos, L; Moreira-Dias, L; Baptista, M; Lopes, C; Castedo, S; Teixeira, M R
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Germline MLH1 and MSH2 mutations are scarce in young colorectal cancer patients with negative family history of the disease. To evaluate the contribution of germline MSH6 mutations to early-onset colorectal cancer, we have analysed peripheral blood of 38 patients diagnosed with this disease before 45 years of age and who presented no family history of hereditary nonpolyposis colorectal cancer-related cancers. Blood samples from 108 healthy volunteers were analysed for those genetic alterations suspected to affect the function of MSH6. Of the seven (18.4%) MSH6 alterations found, we have identified three novel germline mutations, one 8 bp deletion leading to a truncated protein and two missense mutations resulting in the substitution of amino acids belonging to different polarity groups. High-frequency microsatellite instability was found in the patient with the MSH6 deletion, but not in the other 27 carcinomas analysed. No MLH1 promoter methylation was detected in tumour tissue. Our findings suggest that germline MSH6 mutations contribute to a subset of early-onset colorectal cancer. Further studies are warranted to understand the genetic and environmental factors responsible for the variable penetration of MSH6 germline mutations...

‣ Germline mutations of the STK11 gene in Korean Peutz–Jeghers syndrome patients

Yoon, K-A; Ku, J-L; Choi, H S; Heo, S C; Jeong, S-Y; Park, Y J; Kim, N K; Kim, J C; Jung, P M; Park, J-G
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
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Peutz–Jeghers syndrome (PJS) is an autosomal dominantly inherited disease characterized by hamartomatous gastrointestinal polyps and mucocutaneous pigmentation, with an increased risk for various neoplasms, including gastrointestinal cancer. Recently, the PJS gene encoding the serine/threonine kinase STK11 (also named LKB1) was mapped to chromosome 19p13.3, and germline mutations were identified in PJS patients. We screened a total of ten Korean PJS patients (nine sporadic cases and one familial case including two patients) to investigate the germline mutations of the STK11 gene. By polymerase chain reaction–single-strand conformation polymorphism and DNA sequencing analysis, three kinds of mis-sense mutation and a frame-shift mutation were identified: codon 232 (TCC to CCC) in exon 5, codon 256 (GAA to GCA) in exon 6, codon 324 (CCG to CTG) in exon 8, and a guanine insertion at codon 342 resulting in a premature stop codon in exon 8. These mis-sense variants were not detected in 100 control DNA samples. Furthermore, we found an intronic mutation at the dinucleotide sequence of a splice-acceptor site: a one base substitution from AG to CG in intron 1, which may cause aberrant splicing. Most reported germline mutations of the STK11 gene in PJS patients were frame-shift or non-sense mutations resulting in truncated proteins. Together...

‣ Germline Mutations and Variants in the Succinate Dehydrogenase Genes in Cowden and Cowden-like Syndromes

Ni, Ying; Zbuk, Kevin M.; Sadler, Tammy; Patocs, Attila; Lobo, Glenn; Edelman, Emily; Platzer, Petra; Orloff, Mohammed S.; Waite, Kristin A.; Eng, Charis
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
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Individuals with PTEN mutations have Cowden syndrome (CS), associated with breast, thyroid, and endometrial neoplasias. Many more patients with features of CS, not meeting diagnostic criteria (termed CS-like), are evaluated by clinicians for CS-related cancer risk. Germline mutations in succinate dehydrogenase subunits SDHB-D cause pheochromocytoma-paraganglioma syndrome. One to five percent of SDHB/SDHD mutation carriers have renal cell or papillary thyroid carcinomas, which are also CS-related features. SDHB-D may be candidate susceptibility genes for some PTEN mutation-negative individuals with CS-like cancers. To address this hypothesis, germline SDHB-D mutation analysis in 375 PTEN mutation-negative CS/CS-like individuals was performed, followed by functional analysis of identified SDH mutations/variants. Of 375 PTEN mutation-negative CS/CS-like individuals, 74 (20%) had increased manganese superoxide dismutase (MnSOD) expression, a manifestation of mitochondrial dysfunction. Among these, 10 (13.5%) had germline mutations/variants in SDHB (n = 3) or SDHD (7), not found in 700 controls (p < 0.001). Compared to PTEN mutation-positive CS/CS-like individuals, those with SDH mutations/variants were enriched for carcinomas of the female breast (6/9 SDH versus 30/107 PTEN...

‣ Prevalence of Pathological Germline Mutations of hMLH1 and hMSH2 Genes in Colorectal Cancer

Li, Dandan; Hu, Fulan; Wang, Fan; Cui, Binbin; Dong, Xinshu; Zhang, Wencui; Lin, Chunqing; Li, Xia; Wang, Da; Zhao, Yashuang
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 19/03/2013 Português
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The prevalence of pathological germline mutations in colorectal cancer has been widely studied, as germline mutations in the DNA mismatch repair genes hMLH1 and hMSH2 confer a high risk of colorectal cancer. However, because the sample size and population of previous studies are very different from each other, the conclusions still remain controversial. In this paper, Databases such as PubMed were applied to search for related papers. The data were imported into Comprehensive Meta-Analysis V2, which was used to estimate the weighted prevalence of hMLH1 and hMSH2 pathological mutations and compare the differences of prevalence among different family histories, ethnicities and related factors. This study collected and utilized data from 102 papers. In the Amsterdam-criteria positive group, the prevalence of pathological germline mutations of the hMLH1 and hMSH2 genes was 28.55% (95%CI 26.04%–31.19%) and 19.41% (95%CI 15.88%–23.51%), respectively, and the prevalence of germline mutations in hMLH1/hMSH2 was 15.44%/10.02%, 20.43%/13.26% and 15.43%/11.70% in Asian, American multiethnic and European/Australian populations, respectively. Substitution mutations accounted for the largest proportion of germline mutations (hMLH1: 52.34%, hMSH2: 43.25%). The total prevalence of mutations of hMLH1 and hMSH2 in Amsterdam-criteria positive...

‣ Paternal lifestyle as a potential source of germline mutations transmitted to offspring

Linschooten, Joost O.; Verhofstad, Nicole; Gutzkow, Kristine; Olsen, Ann-Karin; Yauk, Carole; Oligschläger, Yvonne; Brunborg, Gunnar; van Schooten, Frederik J.; Godschalk, Roger W. L.
Fonte: Federation of American Societies for Experimental Biology Publicador: Federation of American Societies for Experimental Biology
Tipo: Artigo de Revista Científica
Publicado em /07/2013 Português
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Paternal exposure to high levels of radioactivity causes heritable germline minisatellite mutations. However, the effect of more general paternal exposures, such as cigarette smoking, on germline mutations remains unexplored. We analyzed two of the most commonly used minisatellite loci (CEB1 and B6.7) to identify germline mutations in blood samples of complete mother–father–child triads from the Norwegian Mother and Child Cohort Study (MoBa). The presence of mutations was subsequently related to general lifestyle factors, including paternal smoking before the partner became pregnant. Paternally derived mutations at the B6.7 locus (mutation frequency 0.07) were not affected by lifestyle. In contrast, high gross yearly income as a general measure of a healthy lifestyle coincided with low-mutation frequencies at the CEB1 locus (P=0.047). Income was inversely related to smoking behavior, and paternally derived CEB1 mutations were dose dependently increased when the father smoked in the 6 mo before pregnancy, 0.21 vs. 0.05 in smoking and nonsmoking fathers, respectively (P=0.061). These results suggest that paternal lifestyle can affect the chance of heritable mutations in unstable repetitive DNA sequences. To our knowledge, this is the first study reporting an effect of lifestyle on germline minisatellite mutation frequencies in a human population with moderate paternal exposures.—Linschooten...

‣ ATM-Heterozygous Germline Mutations Contribute to Breast Cancer–Susceptibility

Broeks, Annegien; Urbanus, Jos H. M.; Floore, Arno N.; Dahler, Ellen C.; Klijn, Jan G. M.; Rutgers, Emiel J. Th.; Devilee, Peter; Russell, Nicola S.; van Leeuwen, Flora E.; van 't Veer, Laura J.
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
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Approximately 0.5%–1% of the general population has been estimated to be heterozygous for a germline mutation in the ATM gene. Mutations in the ATM gene are responsible for the autosomal recessive disorder ataxia-telangiectasia (A-T) (MIM 208900). The finding that ATM-heterozygotes have an increased relative risk for breast cancer was supported by some studies but not confirmed by others. In view of this discrepancy, we examined the frequency of ATM germline mutations in a selected group of Dutch patients with breast cancer. We have analyzed ATM germline mutations in normal blood lymphocytes, using the protein-truncation test followed by genomic-sequence analysis. A high percentage of ATM germline mutations was demonstrated among patients with sporadic breast cancer. The 82 patients included in this study had developed breast cancer at age <45 and had survived ⩾5 years (mean 15 years), and in 33 (40%) of the patients a contralateral breast tumor had been diagnosed. Among these patients we identified seven (8.5%) ATM germline mutations, of which five are distinct. One splice-site mutation (IVS10-6T→G) was detected three times in our series. Four heterozygous carriers were patients with bilateral breast cancer. Our results indicate that the mutations identified in this study are “A-T disease–causing” mutations that might be associated with an increased risk of breast cancer in heterozygotes. We conclude that ATM heterozygotes have an approximately ninefold-increased risk of developing a type of breast cancer characterized by frequent bilateral occurrence...

‣ Tumors associated with p53 germline mutations: a synopsis of 91 families.

Kleihues, P.; Schäuble, B.; zur Hausen, A.; Estève, J.; Ohgaki, H.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /01/1997 Português
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Although inherited p53 mutations are present in all somatic cells, malignant transformation is limited to certain organs and target cells. The analysis of 475 tumors in 91 families with p53 germline mutations reported since 1990 shows that breast carcinomas are most frequent (24.0%), followed by bone sarcomas (12.6%), brain tumors (12.0%), and soft tissue sarcomas (11.6%). The sporadic counterparts of these tumors also carry a high incidence of p53 mutations, suggesting that in these tissues p53 mutations are capable of initiating the process of malignant transformation. Hematological neoplasms (acute lymphoblastic leukemia and Hodgkin's lymphoma) and adrenocortical carcinomas occurred at a frequency of 4.2 and 3.6%, respectively. One-half of the families fulfilled the diagnostic criteria of the Li-Fraumeni syndrome. There were marked organ-specific differences in the mean age at which carriers of p53 germline mutations present with neoplastic disease: 5 years for adrenocortical carcinomas, 16 years for sarcomas, 25 years for brain tumors, 37 years for breast cancer, and almost 50 years for lung cancer. Analysis of the mutational spectrum showed a predominance of G:C-->A:T transitions at CpG sites, suggesting an endogenous formation...

‣ Novel germline mutations in the PTEN tumour suppressor gene found in women with multiple cancers

De Vivo, I.; Gertig, D.; Nagase, S.; Hankinson, S.; O'Brien, R.; Speizer, F.; Parsons, R.; Hunter, D.
Fonte: BMJ Group Publicador: BMJ Group
Tipo: Artigo de Revista Científica
Publicado em /05/2000 Português
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Germline mutations in PTEN can predispose people to Cowden syndrome (CS) and Bannayan-Ruvalcaba-Riley (BRR) syndrome, rare, autosomal dominantly inherited neoplastic disorders. To determine whether germline mutations in PTEN contribute to genetic predisposition to multiple primary tumours within the general population, we conducted a nested case-control study, among 32 826 members of the prospective Nurses' Health Study cohort; cases were women with more than one primary tumour at different anatomical sites. We screened all nine exons of PTEN and flanking intronic splice sites for all 103 eligible cases using SSCP and sequencing. We observed two novel germline heterozygous missense mutations in exon 5 in five of the cases; three were V119L and two were V158L. Neither mutation was observed in 115 controls free of diagnosed cancer (p=0.02). Both mutants showed partial tumour suppressor activity when compared to wild type PTEN when transfected into a PTEN null breast cancer cell line. The phenotype was cell line specific suggesting that genetic background affects growth suppression activity of the mutants. These data provide evidence that germline mutations in PTEN may be a more frequent predisposing factor for cancers in women than previously suggested.


Keywords: population based; tumour suppressor; multiple cancers; germline mutations

‣ POLD1 Germline Mutations in Patients Initially Diagnosed with Werner Syndrome

Lessel, Davor; Hisama, Fuki M.; Szakszon, Katalin; Saha, Bidisha; Sanjuanelo, Alexander Barrios; Salbert, Bonnie A.; Steele, Pamela D.; Baldwin, Jennifer; Brown, W. Ted; Piussan, Charles; Plauchu, Henri; Szilvássy, Judit; Horkay, Edit; Hoögel, Josef; Ma
Fonte: PubMed Publicador: PubMed
Tipo: Text
Português
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Segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ. A prototypic example is the Werner syndrome (WS), caused by biallelic germline mutations in the Werner helicase gene (WRN). While heterozygous lamin A/C (LMNA) mutations are found in a few nonclassical cases of WS, another 10%–15% of patients initially diagnosed with WS do not have mutations in WRN or LMNA. Germline POLD1 mutations were recently reported in five patients with another segmental progeroid disorder: mandibular hypoplasia, deafness, progeroid features syndrome. Here, we describe eight additional patients with heterozygous POLD1 mutations, thereby substantially expanding the characterization of this new example of segmental progeroid disorders. First, we identified POLD1 mutations in patients initially diagnosed with WS. Second, we describe POLD1 mutation carriers without clinically relevant hearing impairment or mandibular underdevelopment, both previously thought to represent obligate diagnostic features. These patients also exhibit a lower incidence of metabolic abnormalities and joint contractures. Third, we document postnatal short stature and premature greying/loss of hair in POLD1 mutation carriers. We conclude that POLD1 germline mutations can result in a variably expressed and probably underdiagnosed segmental progeroid syndrome.

‣ Germline TP53 mutations and single nucleotide polymorphisms in children

Valva,Pamela; Becker,Pablo D.; Streitemberger,Patricia; García Lombardi,Mercedes; Rey,Guadalupe; Guzmán,Carlos A.; Preciado,María Victoria
Fonte: Medicina (Buenos Aires) Publicador: Medicina (Buenos Aires)
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/02/2009 Português
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Mutations in the gene TP53, which codifies the tumor suppressor protein p53, are found in about 50% of tumors. These mutations can occur not only at somatic level, but also in germline. Pediatric cancer patients, mostly with additional family history of malignancy, should be considered as potential TP53 germline mutation carriers. Germline TP53 mutations and polymorphisms have been widely studied to determine their relation with different tumors' pathogenesis. Our aim was to analyze the occurrence frequency of germline TP53 mutations and polymorphisms and to relate these to tumor development in a pediatric series. Peripheral blood mononuclear cell samples from 26 children with solid tumors [PST] and 21 pediatric healthy donors [HD] were analyzed for germline mutations and polymorphisms in TP53 gene spanning from exon 5 to 8 including introns 5 and 7. These PCR amplified fragments were sequenced to determine variations. A heterozygous mutation at codon 245 was found in 1/26 PST and 0/21 HD. Comparative polymorphisms distribution, at position 14181 and 14201(intron 7), between HD and PST revealed a trend of association (p= 0.07) with cancer risk. HD group disclosed a similar polymorphism distribution as published data for Caucasian and Central/South American populations. This is the first study about TP53 variant frequency and distribution in healthy individuals and cancer patients in Argentina.