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1.
J Natl Cancer Inst ; 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30312457

RESUMO

Background: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear. Methods: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided. Results: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer. Conclusion: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.

2.
Genes Chromosomes Cancer ; 56(11): 788-799, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28691344

RESUMO

Familial breast cancers (BCs) account for 10%-20% of all diagnosed BCs, yet only 20% of such tumors arise in the context of a germline mutation in known tumor suppressor genes such as BRCA1 or BRCA2. The vast genetic heterogeneity which characterizes non BRCA1 and non BRCA2 (or BRCAx) families makes grouped studies impossible to perform. Next generation sequencing techniques, however, allow individual families to be studied to identify rare and or private mutations but the high number of genetic variants identified need to be sorted using pathogenicity or recurrence criteria. An additional sorting criterion may be represented by the identification of candidate regions defined by tumor genomic rearrangements. Indeed, comparative genomic hybridization (CGH) using single nucleotide polymorphism (SNP) arrays allows the detection of conserved ancestral haplotypes within recurrent regions of loss of heterozygosity, common to several familial tumors, which can highlight genomic loci harboring a germline mutation in cancer predisposition genes. The combination of both exome sequencing and SNP array-CGH for a series of familial BC revealed a germline ATM mutation associated with a loss of the wild-type allele in two BC from a BRCAx family. The analysis of additional breast tumors from ten BC families in which a germline ATM mutation had been identified revealed a high frequency of wild-type allele loss. This result argues strongly in favor of the involvement of ATM in these tumors as a tumor suppressor gene and confirms that germline ATM mutations are involved in a subset of familial BC.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias da Mama/genética , Carcinogênese/genética , Exoma , Mutação em Linhagem Germinativa , Adulto , Idoso , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Neoplasias da Mama/patologia , Feminino , Perfilação da Expressão Gênica , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Polimorfismo de Nucleotídeo Único , Estudo de Prova de Conceito
3.
Eur J Hum Genet ; 25(9): 1087-1091, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28513612

RESUMO

Cowden syndrome (CS) is an inherited autosomal dominant disorder associated with germline pathogenic variants of the PTEN tumor suppressor gene. Its phenotypical expression is highly variable and the existence of patients with a CS suggestive phenotype without pathogenic PTEN variant may be related to genetic heterogeneity. In order to explore this hypothesis through the detection of potentially deleterious variants enabling us to identify a new candidate gene, we performed whole-exome sequencing (WES) in a series of 22 CS patients without detectable PTEN pathogenic variant using conventional methods for mutation screening. We failed to identify a novel candidate gene, but interestingly in two patients WES revealed the presence of two distinct, previously undescribed Alu insertions with the same break points in exon 5. These insertions were not found in a series of 35 breast carcinomas that showed a loss of PTEN expression without a detectable alteration of this gene. This study reveals the presence of a PTEN Alu insertion hotspot involved in CS, and suggests that undetected PTEN pathogenic variants could contribute to CS.


Assuntos
Elementos Alu , Síndrome do Hamartoma Múltiplo/genética , PTEN Fosfo-Hidrolase/genética , Adulto , Exoma , Feminino , Heterogeneidade Genética , Síndrome do Hamartoma Múltiplo/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Mutagênese Insercional , Taxa de Mutação
4.
J Med Genet ; 50(4): 255-63, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23335809

RESUMO

BACKGROUND: PTEN hamartoma tumour syndrome (PHTS) encompasses several clinical syndromes with germline mutations in the PTEN tumour suppressor gene, including Cowden syndrome which is characterised by an increased risk of breast and thyroid cancers. Because PHTS is rare, data regarding cancer risks and genotype-phenotype correlations are limited. The objective of this study was to better define cancer risks in this syndrome with respect to the type and location of PTEN mutations. METHODS: 154 PHTS individuals with a deleterious germline PTEN mutation were recruited from the activity of the Institut Bergonié genetic laboratory. Detailed phenotypic information was obtained for 146 of them. Age and sex adjusted standardised incidence ratio (SIR) calculations, cumulative cancer risk estimations, and genotype-phenotype analyses were performed. RESULTS: Elevated SIRs were found mainly for female breast cancer (39.1, 95% CI 24.8 to 58.6), thyroid cancer in women (43.2, 95% CI 19.7 to 82.1) and in men (199.5, 95% CI 106.39 to 342.03), melanoma in women (28.3, 95% CI 7.6 to 35.4) and in men (39.4, 95% CI 10.6 to 100.9), and endometrial cancer (48.7, 95% CI 9.8 to 142.3). Cumulative cancer risks at age 70 were 85% (95% CI 70% to 95%) for any cancer, 77% (95% CI 59% to 91%) for female breast cancer, and 38% (95% CI 25% to 56%) for thyroid cancer. The risk of cancer was two times greater in women with PHTS than in men with PHTS (p<0.05). CONCLUSIONS: This study shows a considerably high cumulative risk of cancer for patients with PHTS, mainly in women without clear genotype-phenotype correlation for this cancer risk. New recommendations for the management of PHTS patients are proposed.


Assuntos
Síndrome do Hamartoma Múltiplo/complicações , Síndrome do Hamartoma Múltiplo/genética , PTEN Fosfo-Hidrolase/genética , Adulto , Idoso , Neoplasias da Mama/etiologia , Neoplasias da Mama/genética , Neoplasias do Endométrio/genética , Feminino , Estudos de Associação Genética , Mutação em Linhagem Germinativa , Síndrome do Hamartoma Múltiplo/patologia , Humanos , Masculino , Melanoma/etiologia , Melanoma/genética , Pessoa de Meia-Idade , Fatores de Risco , Neoplasias da Glândula Tireoide/etiologia , Neoplasias da Glândula Tireoide/genética
5.
Fam Cancer ; 11(4): 681-3, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22890886

RESUMO

Several studies report an increased risk of breast/pancreatic cancer in MMR (DNA mismatch repair) mutation carriers that has significant consequences on standard cancer screening in such population. The French national network involved in Lynch syndrome molecular characterization registered 15 families with an identified MMR germline mutation and the occurrence of breast/pancreatic adenocarcinoma in mutations carriers. Corresponding tumors were investigated and the MMR function was shown to be intact. This observation tends to exclude breast/pancreatic cancers from Lynch tumor spectrum defined by a complete loss of the MMR function in tumor cells and to support the hypothesis of another causal factor.


Assuntos
Neoplasias da Mama/etiologia , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Reparo de Erro de Pareamento de DNA/genética , Neoplasias Pancreáticas/etiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Técnicas Imunoenzimáticas , Instabilidade de Microssatélites , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias Pancreáticas/diagnóstico , Prognóstico
6.
PLoS One ; 7(12): e52079, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23284877

RESUMO

INTRODUCTION: Germline BRCA1 or BRCA2 mutations account for 20-30% of familial clustering of breast cancer. The main indication for BRCA2 screening is currently the family history but the yield of mutations identified in patients selected this way is low. METHODS: To develop more efficient approaches to screening we have compared the gene expression and genomic profiles of BRCA2-mutant breast tumors with those of breast tumors lacking BRCA1 or BRCA2 mutations. RESULTS: We identified a group of 66 genes showing differential expression in our training set of 7 BRCA2-mutant tumors and in an independent validation set of 19 BRCA2-mutant tumors. The differentially expressed genes include a prominent cluster of genes from chromosomes 13 and 14 whose expression is reduced. Gene set enrichment analysis confirmed that genes in specific bands on 13q and 14q showed significantly reduced expression, suggesting that the affected bands may be preferentially deleted in BRCA2-mutant tumors. Genomic profiling showed that the BRCA2-mutant tumors indeed harbor deletions on chromosomes 13q and 14q. To exploit this information we have created a simple fluorescence in situ hybridization (FISH) test and shown that it detects tumors with deletions on chromosomes 13q and 14q. CONCLUSION: Together with previous reports, this establishes that deletions on chromosomes 13q and 14q are a hallmark of BRCA2-mutant tumors. We propose that FISH to detect these deletions would be an efficient and cost-effective first screening step to identify potential BRCA2-mutation carriers among breast cancer patients without a family history of breast cancer.


Assuntos
Neoplasias da Mama/genética , Deleção Cromossômica , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 14 , Genes BRCA2 , Mutação , Adulto , Idoso , Análise por Conglomerados , Hibridização Genômica Comparativa , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Curva ROC , Reprodutibilidade dos Testes
7.
Cancer Genet Cytogenet ; 157(2): 118-26, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15721632

RESUMO

Chromosomal abnormalities are found by conventional cytogenetic (CC) analysis in about 50% of myelodysplastic syndromes (MDS) and 70% of acute myeloid leukemias (AML). When cytogenetic abnormalities are complex, multiplex fluorescence in situ hybridization (M-FISH) can help clarify complex chromosomal abnormalities and identify rearrangements with prognostic value or cryptic translocations, which could be preliminary steps in identifying new genes. We studied by M-FISH 28 cases of MDS and AML with complex chromosomal abnormalities, 10 of them were therapy-related. M-FISH allowed the characterization of unidentified chromosomal material in 26 cases (93%). One or several unbalanced rearrangements were observed in 27 cases (96%), generally interpreted as deletions or additional material by CC. Among those translocations, 4 involved 3 chromosomes. Eighteen cryptic translocations undetected by CC were found in 13 cases. By FISH analysis using locus specific probes, TP53 deletion, additional copies of MLL, and additional copies or deletions of RUNX1/AML1 were observed in 16, 4, and 3 cases, respectively. Thus, M-FISH is an important tool to characterize complex chromosomal abnormalities which identified unbalanced and cryptic translocations in 96% and 46% of the cases studied, respectively. Complementary FISH helped us identify involvement of TP53, MLL, and RUNX1/AML1 genes in 82% of cases, confirming their probable role in leukemogenesis.


Assuntos
Aberrações Cromossômicas , Hibridização in Situ Fluorescente/métodos , Leucemia Mieloide/genética , Síndromes Mielodisplásicas/genética , Doença Aguda , Adulto , Idoso , Feminino , Humanos , Cariotipagem , Masculino , Pessoa de Meia-Idade
8.
Ann Genet ; 45(3): 165-8, 2002 Jul-Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12381451

RESUMO

Cytogenetic analysis of mantle cell lymphoma (MCL), characterized by the presence of t(11;14)(q13;q32) translocation, is often difficult because of the low proliferating rate of MCL cells and the presence of normal cells in bone marrow which may interfere with growth of MCL cells. We describe herein a TPA (12-O-tetradecanoylphorbol 13-acetate) stimulated culture to improve detection of t(11;14)(q13;q32) in 20 MCL patients regardless of the samples used.


Assuntos
Cromossomos Humanos Par 11 , Cromossomos Humanos Par 14 , Linfoma de Célula do Manto/genética , Translocação Genética , Adulto , Idoso , Técnicas de Cultura de Células/métodos , Feminino , Humanos , Linfoma de Célula do Manto/diagnóstico , Masculino , Pessoa de Meia-Idade , Acetato de Tetradecanoilforbol/farmacologia , Células Tumorais Cultivadas
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