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1.
Nat Commun ; 12(1): 1277, 2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33627649

RESUMO

Therapeutic antibodies are transforming the treatment of cancer and autoimmune diseases. Today, a key challenge is finding antibodies against new targets. Phenotypic discovery promises to achieve this by enabling discovery of antibodies with therapeutic potential without specifying the molecular target a priori. Yet, deconvoluting the targets of phenotypically discovered antibodies remains a bottleneck; efficient deconvolution methods are needed for phenotypic discovery to reach its full potential. Here, we report a comprehensive investigation of a target deconvolution approach based on pooled CRISPR/Cas9. Applying this approach within three real-world phenotypic discovery programs, we rapidly deconvolute the targets of 38 of 39 test antibodies (97%), a success rate far higher than with existing approaches. Moreover, the approach scales well, requires much less work, and robustly identifies antibodies against the major histocompatibility complex. Our data establish CRISPR/Cas9 as a highly efficient target deconvolution approach, with immediate implications for the development of antibody-based drugs.


Assuntos
Edição de Genes , Anticorpos/metabolismo , Sistemas CRISPR-Cas/genética , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Humanos
2.
Leukemia ; 34(12): 3439, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32665696

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

3.
Leukemia ; 34(12): 3323-3337, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32555370

RESUMO

The fate options of hematopoietic stem cells (HSCs) include self-renewal, differentiation, migration, and apoptosis. HSCs self-renewal divisions in stem cells are required for rapid regeneration during tissue damage and stress, but how precisely intracellular calcium signals are regulated to maintain fate options in normal hematopoiesis is unclear. S100A6 knockout (KO) HSCs have reduced total cell numbers in the HSC compartment, decreased myeloid output, and increased apoptotic HSC numbers in steady state. S100A6KO HSCs had impaired self-renewal and regenerative capacity, not responding to 5-Fluorouracil. Our transcriptomic and proteomic profiling suggested that S100A6 is a critical HSC regulator. Intriguingly, S100A6KO HSCs showed decreased levels of phosphorylated Akt (p-Akt) and Hsp90, with an impairment of mitochondrial respiratory capacity and a reduction of mitochondrial calcium levels. We showed that S100A6 regulates intracellular and mitochondria calcium buffering of HSC upon cytokine stimulation and have demonstrated that Akt activator SC79 reverts the levels of intracellular and mitochondrial calcium in HSC. Hematopoietic colony-forming activity and the Hsp90 activity of S100A6KO are restored through activation of the Akt pathway. We show that p-Akt is the prime downstream mechanism of S100A6 in the regulation of HSC self-renewal by specifically governing mitochondrial metabolic function and Hsp90 protein quality.

4.
Leukemia ; 34(3): 697-708, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31913320

RESUMO

Multiple myeloma (MM) is the second most common blood malignancy. Epidemiological family studies going back to the 1920s have provided evidence for familial aggregation, suggesting a subset of cases have an inherited genetic background. Recently, studies aimed at explaining this phenomenon have begun to provide direct evidence for genetic predisposition to MM. Genome-wide association studies have identified common risk alleles at 24 independent loci. Sequencing studies of familial cases and kindreds have begun to identify promising candidate genes where variants with strong effects on MM risk might reside. Finally, functional studies are starting to give insight into how identified risk alleles promote the development of MM. Here, we review recent findings in MM predisposition field, and highlight open questions and future directions.


Assuntos
Predisposição Genética para Doença , Mieloma Múltiplo/genética , Alelos , Ensaios Clínicos como Assunto , Variação Genética , Genoma Humano , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Mieloma Múltiplo/epidemiologia , Polimorfismo de Nucleotídeo Único , Risco , Análise de Sequência de DNA
5.
Commun Biol ; 2: 262, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31341961

RESUMO

The landscape of somatic acquired deletions in cancer cells is shaped by positive and negative selection. Recurrent deletions typically target tumor suppressor, leading to positive selection. Simultaneously, loss of a nearby essential gene can lead to negative selection, and introduce latent vulnerabilities specific to cancer cells. Here we show that, under basic assumptions on positive and negative selection, deletion limitation gives rise to a statistical pattern where the frequency of homozygous deletions decreases approximately linearly between the deletion target gene and the nearest essential genes. Using DNA copy number data from 9,744 human cancer specimens, we demonstrate that linear deletion limitation exists and exposes deletion-limiting genes for seven known deletion targets (CDKN2A, RB1, PTEN, MAP2K4, NF1, SMAD4, and LINC00290). Downstream analysis of pooled CRISPR/Cas9 data provide further evidence of essentiality. Our results provide further insight into how the deletion landscape is shaped and identify potentially targetable vulnerabilities.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Deleção de Genes , Genes Essenciais , Homozigoto , Neoplasias Pulmonares/genética , Linhagem Celular Tumoral , DNA/genética , Dosagem de Genes , Genoma Humano , Células HEK293 , Humanos , Modelos Lineares , RNA/metabolismo
7.
Oncotarget ; 7(48): 78827-78840, 2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-27705932

RESUMO

The utility of KRAS mutations in plasma circulating cell-free DNA (cfDNA) samples as non-invasive biomarkers for the detection of pancreatic cancer has never been evaluated in a large case-control series. We applied a KRAS amplicon-based deep sequencing strategy combined with analytical pipeline specifically designed for the detection of low-abundance mutations to screen plasma samples of 437 pancreatic cancer cases, 141 chronic pancreatitis subjects, and 394 healthy controls. We detected mutations in 21.1% (N=92) of cases, of whom 82 (89.1%) carried at least one mutation at hotspot codons 12, 13 or 61, with mutant allelic fractions from 0.08% to 79%. Advanced stages were associated with an increased proportion of detection, with KRAS cfDNA mutations detected in 10.3%, 17,5% and 33.3% of cases with local, regional and systemic stages, respectively. We also detected KRAS cfDNA mutations in 3.7% (N=14) of healthy controls and in 4.3% (N=6) of subjects with chronic pancreatitis, but at significantly lower allelic fractions than in cases. Combining cfDNA KRAS mutations and CA19-9 plasma levels on a limited set of case-control samples did not improve the overall performance of the biomarkers as compared to CA19-9 alone. Whether the limited sensitivity and specificity observed in our series of KRAS mutations in plasma cfDNA as biomarkers for pancreatic cancer detection are attributable to methodological limitations or to the biology of cfDNA should be further assessed in large case-control series.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , DNA Tumoral Circulante/genética , Mutação , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Idoso , Biomarcadores Tumorais/sangue , Antígeno CA-19-9/sangue , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/patologia , Estudos de Casos e Controles , DNA Tumoral Circulante/sangue , República Tcheca , Análise Mutacional de DNA , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/patologia , Fenótipo , Projetos Piloto , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas p21(ras)/sangue , Reprodutibilidade dos Testes , Eslováquia
8.
J Med Genet ; 53(5): 298-309, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26921362

RESUMO

BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Mutação , RNA Helicases/genética , Adulto , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi , Feminino , Estudos de Associação Genética , Humanos , Pessoa de Meia-Idade , Risco
9.
PLoS One ; 10(9): e0136505, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26352266

RESUMO

The MYD88 L265P is a recurrent somatic mutation in neoplastic cells from patients with Waldenström Macroglobulinemia (WM). We identified the MYD88 L265P mutation in three individuals from unrelated families, but its presence did not explain the disease segregation within these WM pedigrees. We observed the mutation in these three individuals at high allele fractions in DNA extracted from EBV-immortalized Lymphoblastoid cell lines established from peripheral blood (LCL), but at much lower allele fractions in DNA extracted directly from peripheral blood, suggesting that this mutation is present in a clonal cell subpopulation rather than of germ-line origin. Furthermore, we observed that the MYD88 L265P mutation is enriched in WM families, detected in 40.5% of patients with familial WM or MGUS (10/22 WM, 5/15 MGUS), compared to 3.5% of patients with familial MM or MGUS (0/72 MM, 4/41 MGUS) (p = 10-7). The mutant allele frequency increased with passages in vitro after immortalization with Epstein-Barr virus (EBV) consistent with the MYD88 L265P described gain-of-function proposed for this mutation. The MYD88 L265P mutation appears to be frequently present in circulating cells in patients with WM, and MGUS, and these cells are amenable to immortalization by EBV.


Assuntos
Transformação Celular Viral , Células Clonais/patologia , Linfócitos/patologia , Mutação de Sentido Incorreto , Fator 88 de Diferenciação Mieloide/genética , Mutação Puntual , Macroglobulinemia de Waldenstrom/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Divisão Celular , Células Cultivadas , Células Clonais/metabolismo , Células Clonais/virologia , Feminino , Predisposição Genética para Doença , Herpesvirus Humano 4/fisiologia , Humanos , Imunoglobulina M/genética , Linfócitos/metabolismo , Linfócitos/virologia , Masculino , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/sangue , Gamopatia Monoclonal de Significância Indeterminada/genética , Gamopatia Monoclonal de Significância Indeterminada/patologia , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/genética
10.
PLoS One ; 10(4): e0123700, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25849217

RESUMO

BACKGROUND: French Polynesia has one of the highest incidence rates of thyroid cancer worldwide. Relationships with the atmospheric nuclear weapons tests and other environmental, biological, or behavioral factors have already been reported, but genetic susceptibility has yet to be investigated. We assessed the contribution of polymorphisms at the 9q22.33 and 14q13.3 loci identified by GWAS, and within the DNA repair gene ATM, to the risk of differentiated thyroid cancer (DTC) in 177 cases and 275 matched controls from the native population. PRINCIPAL FINDINGS: For the GWAS SNP rs965513 near FOXE1, an association was found between genotypes G/A and A/A, and risk of DTC. A multiplicative effect of allele A was even noted. An excess risk was also observed in individuals carrying two long alleles of the poly-alanine tract expansion in FOXE1, while no association was observed with rs1867277 falling in the promoter region of the gene. In contrast, the GWAS SNP rs944289 (NKX2-1) did not show any significant association. Although the missense substitution D1853N (rs1801516) in ATM was rare in the population, carriers of the minor allele (A) also showed an excess risk. The relationships between these five polymorphisms and the risk of DTC were not contingent on the body surface area, body mass index, ethnicity or dietary iodine intake. However, an interaction was evidenced between the thyroid radiation dose and rs944289. SIGNIFICANCE: A clear link could not be established between the high incidence in French Polynesia and the studied polymorphisms, involved in susceptibility to DTC in other populations. Important variation in allele frequencies was observed in the Polynesian population as compared to the European populations. For FOXE1 rs965513, the direction of association and the effect size was similar to that observed in other populations, whereas for ATM rs1801516, the minor allele was associated to an increased risk in the Polynesian population and with a decreased risk in the European population.


Assuntos
Adenocarcinoma Folicular/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Carcinoma Papilar/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 9/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Glândula Tireoide/genética , Adenocarcinoma Folicular/epidemiologia , Adulto , Carcinoma Papilar/epidemiologia , Estudos de Casos e Controles , Diferenciação Celular , Feminino , Fatores de Transcrição Forkhead/genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Polinésia/epidemiologia , Fatores de Risco , Neoplasias da Glândula Tireoide/epidemiologia , Fator Nuclear 1 de Tireoide , Fatores de Transcrição/genética
11.
BMC Genet ; 16: 22, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25879635

RESUMO

BACKGROUND: The incidence of differentiated thyroid carcinoma (DTC) in Cuba is low and the contribution of host genetic factors to DTC in this population has not been investigated so far. Our goal was to assess the role of known risk polymorphisms in DTC cases living in Havana. We genotyped five polymorphisms located at the DTC susceptibility loci on chromosome 14q13.3 near NK2 homeobox 1 (NKX2-1), on chromosome 9q22.33 near Forkhead factor E1 (FOXE1) and within the DNA repair gene Ataxia-Telangiectasia Mutated (ATM) in 203 cases and 212 age- and sex- matched controls. Potential interactions between these polymorphisms and other DTC risk factors such as body surface area, body mass index, size, ethnicity, and, for women, the parity were also examined. RESULTS: Significant association with DTC risk was found for rs944289 near NKX2-1 (OR per A allele = 1.6, 95% CI: 1.2-2.1), and three polymorphisms near or within FOXE1, namely rs965513 (OR per A allele = 1.7, 95% CI: 1.2-2.3), rs1867277 in the promoter region of the gene (OR per A allele = 1.5, 95% CI: 1.1-1.9) and the poly-alanine tract expansion polymorphism rs71369530 (OR per Long Allele = 1.8, 95% CI: 1.3-2.5), only the 2 latter remaining significant when correcting for multiple tests. Overall, no association between DTC and the coding SNP D1853N (rs1801516) in ATM (OR per A Allele = 1.1, 95% CI: 0.7-1.7) was seen. Nevertheless women who had 2 or more pregnancies had a 3.5-fold increase in risk of DTC if they carried the A allele (OR 3.5, 95% CI: 3.2-9.8) as compared to 0.8 (OR 0.8, 95% CI: 0.4-1.6) in those who had fewer than 2. CONCLUSIONS: We confirmed in the Cuban population the role of the loci previously associated with DTC susceptibility in European and Japanese populations through genome-wide association studies. Our results on ATM and the number of pregnancies raise interesting questions on the mechanisms by which oestrogens, or other hormones, alter the DNA damage response and DNA repair through the regulation of key effector proteins such as ATM. Due to the small size of our study and to multiple tests, all these results warrant further investigation.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 9 , Variação Genética , Locos de Características Quantitativas , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Alelos , Cuba/epidemiologia , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Gradação de Tumores , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Risco , Neoplasias da Glândula Tireoide/epidemiologia
12.
Breast Cancer Res ; 16(3): R58, 2014 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-24894818

RESUMO

INTRODUCTION: The MRE11A-RAD50-Nibrin (MRN) complex plays several critical roles related to repair of DNA double-strand breaks. Inherited mutations in the three components predispose to genetic instability disorders and the MRN genes have been implicated in breast cancer susceptibility, but the underlying data are not entirely convincing. Here, we address two related questions: (1) are some rare MRN variants intermediate-risk breast cancer susceptibility alleles, and if so (2) do the MRN genes follow a BRCA1/BRCA2 pattern wherein most susceptibility alleles are protein-truncating variants, or do they follow an ATM/CHEK2 pattern wherein half or more of the susceptibility alleles are missense substitutions? METHODS: Using high-resolution melt curve analysis followed by Sanger sequencing, we mutation screened the coding exons and proximal splice junction regions of the MRN genes in 1,313 early-onset breast cancer cases and 1,123 population controls. Rare variants in the three genes were pooled using bioinformatics methods similar to those previously applied to ATM, BRCA1, BRCA2, and CHEK2, and then assessed by logistic regression. RESULTS: Re-analysis of our ATM, BRCA1, and BRCA2 mutation screening data revealed that these genes do not harbor pathogenic alleles (other than modest-risk SNPs) with minor allele frequencies>0.1% in Caucasian Americans, African Americans, or East Asians. Limiting our MRN analyses to variants with allele frequencies of <0.1% and combining protein-truncating variants, likely spliceogenic variants, and key functional domain rare missense substitutions, we found significant evidence that the MRN genes are indeed intermediate-risk breast cancer susceptibility genes (odds ratio (OR)=2.88, P=0.0090). Key domain missense substitutions were more frequent than the truncating variants (24 versus 12 observations) and conferred a slightly higher OR (3.07 versus 2.61) with a lower P value (0.029 versus 0.14). CONCLUSIONS: These data establish that MRE11A, RAD50, and NBN are intermediate-risk breast cancer susceptibility genes. Like ATM and CHEK2, their spectrum of pathogenic variants includes a relatively high proportion of missense substitutions. However, the data neither establish whether variants in each of the three genes are best evaluated under the same analysis model nor achieve clinically actionable classification of individual variants observed in this study.


Assuntos
Neoplasias da Mama/genética , Proteínas de Ciclo Celular/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Proteínas Nucleares/genética , Hidrolases Anidrido Ácido , Adulto , Substituição de Aminoácidos , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Sequência de Bases , Estudos de Casos e Controles , Quinase do Ponto de Checagem 2/genética , Quebras de DNA de Cadeia Dupla , Reparo do DNA/genética , Feminino , Frequência do Gene , Testes Genéticos , Humanos , Proteína Homóloga a MRE11 , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Isoformas de Proteínas/genética , Alinhamento de Sequência , Análise de Sequência de DNA
13.
Int J Cancer ; 134(7): 1659-68, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24105688

RESUMO

A dramatic increase in the incidence of papillary thyroid carcinoma (PTC) after childhood exposure to ionizing radiation from the Chernobyl nuclear accident has been described as the largest number of tumors of one type due to one cause that have ever occurred. inter-individual variations in response to radiation have been documented and the role of genetics in sporadic PTC is well established, suggesting that genetic factors may also affect the risk of radiation-related PTC. To investigate how environmental and host factors interplay to modify PTC risk, we genotyped 83 cases and 324 matched controls sampled from children living in the area contaminated by fallout from the Chernobyl power plant accident for 19 polymorphisms previously associated with PTC, thyroid biology or radiation-induced second primary tumors. Significant association with PTC was found for rs1801516 (D1853N) in ATM (odds ratio (OR) = 0.34, 95% confidence interval (CI) 0.16, 0.73) and rs1867277 in the promoter region of FOXE1 (OR = 1.55, 95% CI 1.03, 2.34). Analysis of additional polymorphisms confirmed the association between these two genes and PTC. Our findings suggest that both DNA double-strand break repair pathway and thyroid morphogenesis pathway or dysregulation of thyroid differentiated state maintenance are involved in the etiology of PTC, and that the studied genetic polymorphisms and radiation dose appear to act as independent multiplicative risk factors for PTC.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Carcinoma Papilar/genética , Carcinoma/genética , Acidente Nuclear de Chernobyl , Fatores de Transcrição Forkhead/genética , Neoplasias Induzidas por Radiação/genética , Neoplasias da Glândula Tireoide/genética , Adolescente , Carcinoma/etiologia , Carcinoma Papilar/etiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasias Induzidas por Radiação/etiologia , Polimorfismo de Nucleotídeo Único , Radiação Ionizante , Fatores de Risco , Câncer Papilífero da Tireoide , Glândula Tireoide/efeitos da radiação , Neoplasias da Glândula Tireoide/etiologia
14.
PLoS One ; 8(3): e58182, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23536787

RESUMO

Germline mutations in the BRCA1 and BRCA2 genes contribute to approximately 18% of hereditary ovarian cancers conferring an estimated lifetime risk from 15% to 50%. A variable incidence of mutations has been reported for these genes in ovarian cancer cases from different populations. In Greece, six mutations in BRCA1 account for 63% of all mutations detected in both BRCA1 and BRCA2 genes. This study aimed to determine the prevalence of BRCA1 mutations in a Greek cohort of 106 familial ovarian cancer patients that had strong family history or metachronous breast cancer and 592 sporadic ovarian cancer cases. All 698 patients were screened for the six recurrent Greek mutations (including founder mutations c.5266dupC, p.G1738R and the three large deletions of exon 20, exons 23-24 and exon 24). In familial cases, the BRCA1 gene was consequently screened for exons 5, 11, 12, 20, 21, 22, 23, 24. A deleterious BRCA1 mutation was found in 43/106 (40.6%) of familial cancer cases and in 27/592 (4.6%) of sporadic cases. The variant of unknown clinical significance p.V1833M was identified in 9/698 patients (1.3%). The majority of BRCA1 carriers (71.2%) presented a high-grade serous phenotype. Identifying a mutation in the BRCA1 gene among breast and/or ovarian cancer families is important, as it enables carriers to take preventive measures. All ovarian cancer patients with a serous phenotype should be considered for genetic testing. Further studies are warranted to determine the prevalence of mutations in the rest of the BRCA1 gene, in the BRCA2 gene, and other novel predisposing genes for breast and ovarian cancer.


Assuntos
Genes BRCA1 , Mutação , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Adolescente , Adulto , Fatores Etários , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Criança , Éxons , Família , Feminino , Genes BRCA2 , Grécia/epidemiologia , Heterozigoto , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Linhagem , Fenótipo , Prevalência , Adulto Jovem
15.
Breast Cancer Res Treat ; 134(1): 353-62, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22434525

RESUMO

In spite the close association of the triple-negative breast cancer immunophenotype with hereditary breast cancers and the BRCA1 pathway, there is a lack of population studies that determine the frequency of BRCA1 mutations among triple-negative breast cancer patients. To address this, we have screened a large sample of 403 women diagnosed with triple-negative invasive breast cancer, independently of their age or family history, for germline BRCA1 mutations. Median age at diagnosis was 50 years (range 20-83). The overall prevalence of triple-negative cases among the initial patient group with invasive breast cancer was 8%. BRCA1 was screened by direct DNA sequencing in all patients, including all exons where a mutation was previously found in the Greek population (exons 5, 11, 12, 16, 20, 21, 22, 23, 24-77% of the BRCA1 coding region), including diagnostic PCRs to detect the three Greek founder large genomic rearrangements. Sixty-five deleterious BRCA1 mutations were identified among the 403 triple-negative breast cancer patients (16%). Median age of onset for mutation carriers was 39 years. Among a total of 106 women with early-onset triple-negative breast cancer (<40 years), 38 (36%) had a BRCA1 mutation, while 27% of women with triple-negative breast cancer diagnosed before 50 years (56/208) had a BRCA1 mutation. A mutation was found in 48% (50/105) of the triple-negative breast cancer patients with family history of breast or ovarian cancer. It is noteworthy, however, that of the 65 carriers, 15 (23%) had no reported family history of related cancers. All but one of the carriers had grade III tumors (98%). These results indicate that women with early-onset triple-negative breast cancer, and ideally all triple-negative breast cancer patients, are candidates for BRCA1 genetic testing even in the absence of a family history of breast or ovarian cancer.


Assuntos
Proteína BRCA1/genética , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/genética , Testes Genéticos , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/diagnóstico , Carcinoma Lobular/epidemiologia , Carcinoma Lobular/metabolismo , Análise Mutacional de DNA , Feminino , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/metabolismo , Heterozigoto , Humanos , Pessoa de Meia-Idade , Mutação , Seleção de Pacientes , Prevalência , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Adulto Jovem
16.
Breast Cancer Res ; 13(6): R110, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22053997

RESUMO

INTRODUCTION: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. METHODS: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. RESULTS: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. CONCLUSIONS: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.


Assuntos
Alelos , Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Heterozigoto , Mutação , Neoplasias da Mama/classificação , Neoplasias da Mama/metabolismo , Feminino , Humanos , Polimorfismo de Nucleotídeo Único , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Risco
17.
Breast Cancer Res Treat ; 127(3): 671-9, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20652400

RESUMO

The c.156_157insAlu BRCA2 mutation has so far only been reported in hereditary breast/ovarian cancer (HBOC) families of Portuguese origin. Since this mutation is not detectable using the commonly used screening methodologies and must be specifically sought, we screened for this rearrangement in a total of 5,443 suspected HBOC families from several countries. Whereas the c.156_157insAlu BRCA2 mutation was detected in 11 of 149 suspected HBOC families from Portugal, representing 37.9% of all deleterious mutations, in other countries it was detected only in one proband living in France and in four individuals requesting predictive testing living in France and in the USA, all being Portuguese immigrants. After performing an extensive haplotype study in carrier families, we estimate that this founder mutation occurred 558 ± 215 years ago. We further demonstrate significant quantitative differences regarding the production of the BRCA2 full length RNA and the transcript lacking exon 3 in c.156_157insAlu BRCA2 mutation carriers and in controls. The cumulative incidence of breast cancer in carriers did not differ from that of other BRCA2 and BRCA1 pathogenic mutations. We recommend that all suspected HBOC families from Portugal or with Portuguese ancestry are specifically tested for this rearrangement.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Genes BRCA2 , Mutação , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Sequência de Aminoácidos , Feminino , Efeito Fundador , Predisposição Genética para Doença , Testes Genéticos , Genética Populacional , Humanos , Repetições de Microssatélites , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Portugal/epidemiologia , RNA Mensageiro/análise , Fases de Leitura/genética , Deleção de Sequência
18.
Breast Cancer Res Treat ; 110(2): 377-85, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17902052

RESUMO

We have performed screening in 287 breast/ovarian cancer families in Greece which has revealed that approximately 12% (8/65) of all index patients-carriers of a deleterious mutation in BRCA1 and BRCA2 genes, contain the base substitution G to A at position 5331 of BRCA1 gene. This generates the amino acid change G1738R for which based on a combination of genetic, in silico and histopathological analysis there are strong suggestions that it is a causative mutation. In this paper, we present further evidence suggesting the pathogenicity of this variant. Forty breast/ovarian cancer patients were reported in 11 Greek families: the above eight living in Greece, two living in Australia and one in USA, all containing G1738R. Twenty of these patients were screened and were all found to be carriers of the same base substitution. In addition, we have detected the same base change in five breast/ovarian cancer patients after screening 475 unselected patient samples with no apparent family history. The mean age of onset for all the above patients was 39.4 and 53.6 years for breast and ovarian cancer cases, respectively. A multi-factorial likelihood model for classification of unclassified variants in BRCA1 and BRCA2 developed previously was applied on G1738R and the odds of it being a deleterious mutation was estimated to be 11470:1. In order to explain the prevalence of this mutation mainly in the Greek population, its genealogical history was examined. DNA samples were collected from 11 carrier families living in Greece, Australia and USA. Screening of eight intragenic SNPs, three intragenic and seven extragenic microsatellite markers and comparison with control individuals, suggested a common origin for the mutation while the time to its most recent common ancestor was estimated to be 11 generations (about 275 years assuming a generational interval of 25 years) with a 1-lod support interval of 4-24 generations (100-600 years). Considering the large degree of genetic heterogeneity in the Greek population, the identification of a frequent founder mutation greatly facilitates genetic screening.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/etnologia , Neoplasias da Mama/genética , Genes BRCA1 , Mutação , Neoplasias Ovarianas/etnologia , Neoplasias Ovarianas/genética , Adulto , Idade de Início , Saúde da Família , Feminino , Predisposição Genética para Doença , Testes Genéticos , Humanos , Funções Verossimilhança , Repetições de Microssatélites , Pessoa de Meia-Idade
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