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1.
Mol Carcinog ; 58(1): 156-160, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30230034

RESUMO

BRIP1 is a component of the Fanconi Anemia/BRCA pathway responsible for DNA reparation via helicase activity. Some heterozygous variants in BRIP1 could contribute to Hereditary Breast Cancer through a defective DNA repair. The clinical utility of BRIP1 mutations in a familial cancer context is compromised by the conflicting interpretation of "variants of uncertain significance" (VUS). Defining the clinical significance of variants identified in genetic tests is a major challenge; therefore, studies that evaluate the biological effect of these variants are definitely necessary. To contribute to this purpose, we have characterized the variant c.550G>T of BRIP1, a missense mutation with little evidence about its pathogenicity. Since Human Splicing FinderTM predicts the creation of a new exonic splicing enhancer site we decided to perform cDNA analysis revealing that the c.550G>T mutation located in exon 6 led to an aberrant transcript causing exon 5 skipping. Our results demonstrate that the c.550G>T BRIP1 variant disrupts normal splicing, causing exon 5 skipping. Considering that the exon 5 encodes the helicase domain of BRIP1, it is expected an alteration of the function. This finding enhances the interpretation of this VUS, suggesting a potential pathogenic effect.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Predisposição Genética para Doença , Mutação de Sentido Incorreto , RNA Helicases/genética , Feminino , Humanos , Pessoa de Meia-Idade , Linhagem , Prognóstico
2.
Breast ; 43: 91-96, 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30521987

RESUMO

Explaining genetic predisposition in Hereditary Breast and Ovarian Cancer (HBOC) families without BRCA mutations is crucial. Germline PALB2 inactivating mutations were associated with an increased risk of HBOC due to its role in DNA repair through cooperation with BRCA proteins. The prevalence and penetrance of PALB2 mutations in Spanish HBOC patients remains unexplained. PALB2 mutation screening has been conducted in 160 high-risk BRCA-negative patients and 320 controls. We evaluated four predicted splicing disruption variants and large genomic rearrangements by multiplex ligation-dependent probe amplification. We have found a frameshift mutation which segregates in an early onset cancer family; and four rare missense variants. None of the variants tested for a predicted splicing disruption showed an aberrant transcript pattern. No large genomic rearrangements were detected. Although PALB2 truncating mutations are rarely identified, segregation analysis and early onset cancer suggest a significant contribution to HBOC susceptibility in the Spanish population. PALB2 screening may improve genetic counselling through prevention measures, pedigree management and PARP inhibitor therapy selection.

3.
Hum Mutat ; 39(9): 1155-1160, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29969168

RESUMO

Many BRCA1 and BRCA2 (BRCA1/2) genetic variants have been studied at mRNA level and linked to hereditary breast and ovarian cancer due to splicing alteration. In silico tools are reliable when assessing variants located in consensus splice sites, but we may identify variants in complex genomic contexts for which bioinformatics is not precise enough. In this study, we characterize BRCA2 c.7976 + 5G > T variant located in intron 17 which has an atypical donor site (GC). This variant was identified in three unrelated Spanish families and we have detected exon 17 skipping as the predominant transcript occurring in carriers. We have also detected several isoforms (Δ16-18, Δ17,18, Δ18, and ▼17q224 ) at different expression levels among carriers and controls. This study remarks the challenge of interpreting genetic variants when multiple alternative isoforms are present, and that caution must be taken when using in silico tools to identify potential spliceogenic variants located in GC-AG introns.

4.
Artigo em Inglês | MEDLINE | ID: mdl-29766361

RESUMO

PURPOSE: Promoter mutations may affect transcription and can be associated with human diseases. However, the promoters of the breast cancer (BC) genes are not regularly screened. Our goal was to investigate the BRCA2 promoter in order to study a possible correlation between impaired transcription and disease. METHODS: The proximal and core promoter of the BRCA2 gene was sequenced in 95 high-risk BC patients. A BRCA2-promoter insert [- 938 to + 312 from the transcription start site (TSS)] was generated and cloned into the firefly luciferase vector pGL4.10. Promoter variants and deletions were introduced by site-directed mutagenesis and quantified by Dual-Luciferase assays and semi-quantitative RT-PCR. RESULTS: Three different variants were detected in high-risk BC patients: rs3092989, rs206118, and rs563971900. Functional mapping of 13 overlapping deletions revealed four down-regulating segments (TSS positions): -59_-10del/µdel3 (16% of activity of the wild-type construct), -104_-55del/µdel4 (62%), -239_-190del/µdel7 (39%), -464_-415/µdel12 (78%), suggesting the presence therein of putative transcriptional activator motifs. Additionally, six microdeletions rendered luciferase overexpression: +32_+81del/µdel1 (356%), -14_+36del/µdel2 (180%), -194_-145del/µdel6 (154%), -284_-235del/µdel8 (168%), -329_-280del/µdel9 (111%), and -509_-460del/µdel13 (139%), which is indicative of repressor elements. Functional assays of 15 promoter variants (including those detected in patients) showed that ten of them significantly altered expression with seven up-regulating (113-163%) and three down-regulating (rs551887850_G, rs570548398_T, rs55880202_T; 72-83%) SNPs. Eight of them were located in an ENCODE-DNase Hypersensitive Cluster (TSS - 185 to + 105) where most active transcriptional motifs are known to be placed. CONCLUSIONS: BRCA2 expression is highly sensitive to promoter variations as most of them induced relevant changes. Moreover, we mapped critical regions of the BRCA2 promoter that may constitute potential targets for regulatory variants. Three SNPs moderately decreased luciferase activity, but confirmation of its potential pathogenicity requires further analysis. These data reinforce the need to screen the promoter regions of breast cancer genes with a view to discovering novel deleterious mutations.

5.
Nature ; 553(7689): 467-472, 2018 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-29342134

RESUMO

Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.


Assuntos
Instabilidade Cromossômica , Citosol/metabolismo , DNA de Neoplasias/metabolismo , Metástase Neoplásica/genética , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/secundário , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular , Instabilidade Cromossômica/genética , Segregação de Cromossomos , Citosol/enzimologia , Feminino , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Inflamação/genética , Inflamação/metabolismo , Proteínas de Membrana/metabolismo , Mesoderma/metabolismo , Camundongos , Micronúcleos com Defeito Cromossômico , NF-kappa B/metabolismo , Nucleotidiltransferases/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Interpers Violence ; 33(14): 2180-2196, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26763287

RESUMO

Sexual assault affects a large proportion of women in the world. Although most rapes are committed by one man, the act itself may be influenced by many (e.g., the peer group). Hostile sexism (HS) has repeatedly been associated with men's rape proclivity, but the influence exerted by the HS of the peer group on rape proclivity has not been investigated. In this study, we explored the impact of perceived male peer support to HS on participants' rape proclivity. A sample of Spanish undergraduate students from a university in the south of Spain ( N = 134) completed the Ambivalent Sexism Inventory. Immediately afterwards, they received feedback on the supposed sexist responses of a peer group (high vs. low in HS); we kept the benevolent sexism (BS) of the peer group at medium levels. Next, we assessed participants' rape proclivity using acquaintance rape scenarios. Results showed an interaction between participants' own levels of HS and information about the HS of the peer group. Men high in HS reported higher rape proclivity in the high-HS peer-group condition than in the low-HS peer-group condition. By contrast, information on the peer group did not affect self-reported rape proclivity of men low in HS. Results also corroborated the relationship between participants' levels of HS and rape proclivity, and expanded the literature by revealing an unexpected influence of participants' BS on rape proclivity.

7.
Gastroenterology ; 154(1): 181-194.e20, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28912018

RESUMO

BACKGROUND & AIMS: Although there is a genetic predisposition to colorectal cancer (CRC), few of the genes that affect risk have been identified. We performed whole-exome sequence analysis of individuals in a high-risk family without mutations in genes previously associated with CRC risk to identify variants associated with inherited CRC. METHODS: We collected blood samples from 3 relatives with CRC in Spain (65, 62, and 40 years old at diagnosis) and performed whole-exome sequence analyses. Rare missense, truncating or splice-site variants shared by the 3 relatives were selected. We used targeted pooled DNA amplification followed by next generation sequencing to screen for mutations in candidate genes in 547 additional hereditary and/or early-onset CRC cases (502 additional families). We carried out protein-dependent yeast growth assays and transfection studies in the HT29 human CRC cell line to test the effects of the identified variants. RESULTS: A total of 42 unique or rare (population minor allele frequency below 1%) nonsynonymous genetic variants in 38 genes were shared by all 3 relatives. We selected the BRF1 gene, which encodes an RNA polymerase III transcription initiation factor subunit for further analysis, based on the predicted effect of the identified variant and previous association of BRF1 with cancer. Previously unreported or rare germline variants in BRF1 were identified in 11 of 503 CRC families, a significantly greater proportion than in the control population (34 of 4300). Seven of the identified variants (1 detected in 2 families) affected BRF1 mRNA splicing, protein stability, or expression and/or function. CONCLUSIONS: In an analysis of families with a history of CRC, we associated germline mutations in BRF1 with predisposition to CRC. We associated deleterious BRF1 variants with 1.4% of familial CRC cases, in individuals without mutations in high-penetrance genes previously associated with CRC. Our findings add additional evidence to the link between defects in genes that regulate ribosome synthesis and risk of CRC.


Assuntos
Neoplasias Colorretais/genética , Mutação em Linhagem Germinativa/genética , Fatores Associados à Proteína de Ligação a TATA/genética , Adulto , Idoso , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Espanha
8.
J Interpers Violence ; 2016 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-27118344

RESUMO

Cyberbullying is attracting social, political, and academic interest as the use of electronic devices such as computers and mobile phones by young people has increased dramatically. However, little is known about the factors involved in their perpetration, particularly in the context of college students' dating relationships. The aim of this study is to examine the involvement of college students in cyberbullying in the context of their dating relationships and to explore the impact of sexism on males' cyberbullying of their girlfriends. Participants are 219 undergraduate students from a university in the south of Spain. Results showed that 48.4% of participants reported having bullied their partners during the last year via mobile phone and 37.5% via Internet. Males reported a greater extent of cyberbullying of their girlfriends through both means. Regression analyses indicated that males' levels of hostile sexism are related to males' cyberbullying of their girlfriends. These findings suggest a modernization in the forms of violence toward women among college students and also expand current literature by revealing the influence of participants' hostile sexism on this type of cyber aggression against women in dating relationships.

9.
Gastroenterology ; 149(3): 563-6, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26052075

RESUMO

Identification of genes associated with hereditary cancers facilitates management of patients with family histories of cancer. We performed exome sequencing of DNA from 3 individuals from a family with colorectal cancer who met the Amsterdam criteria for risk of hereditary nonpolyposis colorectal cancer. These individuals had mismatch repair-proficient tumors and each carried nonsense variant in the FANCD2/FANCI-associated nuclease 1 gene (FAN1), which encodes a nuclease involved in DNA inter-strand cross-link repair. We sequenced FAN1 in 176 additional families with histories of colorectal cancer and performed in vitro functional analyses of the mutant forms of FAN1 identified. We detected FAN1 mutations in approximately 3% of families who met the Amsterdam criteria and had mismatch repair-proficient cancers with no previously associated mutations. These findings link colorectal cancer predisposition to the Fanconi anemia DNA repair pathway, supporting the connection between genome integrity and cancer risk.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo do DNA/genética , Exodesoxirribonucleases/genética , Mutação em Linhagem Germinativa , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Pré-Escolar , Neoplasias Colorretais Hereditárias sem Polipose/enzimologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Exodesoxirribonucleases/metabolismo , Feminino , Predisposição Genética para Doença , Células HEK293 , Hereditariedade , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Adulto Jovem
10.
Fam Cancer ; 14(4): 505-13, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26026974

RESUMO

Male breast cancer (MBC) is a rare disease that represents <1% of all breast cancers (BCs). We analyze the results of a multicenter study performed in Spanish familial MBC including family history of hereditary breast and ovarian cancer syndrome (HBOCS) and clinicopathological features. We also study the relationship between BRCA1/BRCA2 mutational status in male relatives affected with cancer (MAC) and, family history and tumor types. The study included 312 men index cases with family history of HBOCS and 61 MAC BRCA1/2 mutation-carriers. Family history, histological grade (HG), clinicopathological and immunohistochemistry data were collected. BRCA1/2 mutation analyses were performed by direct sequencing or screening methods and the large rearrangements by multiplex ligation dependent probe amplification. We found 49 mutation-carriers (15.7%), 95.9% with BRCA2 mutations. BRCA2 mutation-carriers were associated with families with at least one MBC and one BC in female (type II; p = 0.05). Strong association were found between the presence of pathogenic mutations in MBCs and the advanced HG (p = 0.003). c.658_659delTG, c.2808_2811delACAA, c.6275_6276delTT and c.9026_9030delATCAT were the most prevalent mutations. In 61 MAC we found 20 mutations in BRCA1 and 41 in BRCA2. For MAC we show that mutational status was differentially associated with family history (p = 0.018) and tumor type, being BRCA2 mutations linked with BC and prostatic cancer (p = 0.018). MBC caused by BRCA1/2 mutations define two types of MBCs. The most frequent caused by BRCA2 mutation linked to type II families and the rarest one attributed to BRCA1 mutation. Tumor associated with MAC suggest that only BRCA2 mutations have to do with a specific type of cancer (BC and prostatic cancer); but the linkage to tumors is questionable for BRCA1 mutations .


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama Masculina/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama Masculina/epidemiologia , Neoplasias da Mama Masculina/patologia , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/epidemiologia , Carcinoma Lobular/genética , Carcinoma Lobular/patologia , Feminino , Seguimentos , Testes Genéticos/métodos , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/patologia , Prognóstico , Espanha/epidemiologia , Síndrome , Adulto Jovem
11.
An. psicol ; 31(1): 260-267, ene. 2015. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-131620

RESUMO

El objetivo de este trabajo fue estudiar, desde el paradigma de usos y gratificaciones, el uso que jóvenes españoles (N = 221) hacen de la red social Tuenti, y en qué medida estos usos se asocian con sus niveles de adicción a dicha red social. Además se analizó el papel que los progenitores tienen como facilitadores o inhibidores de dichas tendencias adictivas y el impacto del género. Los resultados muestran cuatro categorías de usos de la red Tuenti: entretenimiento, comunicación a través del muro, comunicación a nivel privado e información social. Además, la actitud positiva hacia la presencia de la madre en la red Tuenti se muestra como un factor de protección de las tendencias adictivas a la red. Por último, se han encontrado diferencias estadísticamente significativas en función del género, tanto en los usos que realizan chicos y chicas, como en sus patrones de adicción a la red Tuenti, de tal manera que los chicos informan de niveles de adicción superiores a los informados por las chicas en el uso de esta red social (AU)


The present work aimed to study, from the uses and gratifications paradigm, the uses that Spanish university students (N = 221) do of the social networking site Tuenti, and the relationship between these uses and young's self-reported levels of addiction towards Tuenti. Also, the students ‘attitudes towards the presence of their parents as contacts in Tuenti, and the impact of gender were analyzed. The results showed four different categories of uses: entertainment, public communication, private communication and social information. Also, young's positive attitude toward the presence of the mother in Tuenti played a protective role in their addition levels towards this social networking site. Finally, statistically significant gender differences in the uses of Tuenti and also in their addiction levels toward Tuenti were found (AU)


Assuntos
Humanos , Comportamento Aditivo/psicologia , Rede Social , Internet , Relações Mãe-Filho , Mães/estatística & dados numéricos , Distribuição por Idade e Sexo
12.
PLoS Genet ; 10(4): e1004256, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24698998

RESUMO

Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 × 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , DNA Glicosilases/genética , Reparo do DNA/genética , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Pessoa de Meia-Idade , Risco
13.
Breast Cancer Res ; 16(6): 3416, 2014 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-25919761

RESUMO

INTRODUCTION: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. METHODS: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. RESULTS: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10(-6) in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. CONCLUSIONS: Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.


Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/genética , Genes BRCA1 , Genes BRCA2 , Adulto , Idoso , Alelos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo
14.
Hum Mutat ; 35(1): 50-2, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24115450

RESUMO

Previous evidence indicates that mutations in the GALNT12 gene might cause a fraction of the unexplained familial colorectal cancer (CRC) cases: GALNT12 is located in 9q22-33, in close proximity to a CRC linkage peak; and germline missense variants that reduce the enzymatic activity of the protein have been identified in CRC patients, some of them with familial CRC history. We hypothesized that mutations in GALNT12 might explain part of the high-risk families grouped as familial CRC type X (fCRC-X), that is, Amsterdam-positive families with mismatch repair proficient tumors. We sequenced the coding regions of the gene in 103 probands of fCRC-X families, finding no functionally relevant mutations. Our results rule out GALNT12 as a major high CRC susceptibility gene. Additional studies are required to provide further evidence about its role as a moderate/low susceptibility gene in familial aggregation of cancer.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , N-Acetilgalactosaminiltransferases/genética , Regiões 3' não Traduzidas , Cromossomos Humanos Par 9/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Reparo de Erro de Pareamento de DNA , Éxons , Predisposição Genética para Doença , Variação Genética , Humanos , Mutação de Sentido Incorreto , N-Acetilgalactosaminiltransferases/metabolismo , Penetrância , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
15.
J Interpers Violence ; 29(8): 1380-401, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24255065

RESUMO

This article describes three studies in which we explored the influence of the sexist ideology attributed to the perpetrator on women's responses to hypothetical acts of sexual assault perpetrated by male intimate partners. In Study 1 (n = 83), college women read three sexual assault scenarios in the context of an intimate relationship. The male partner's sexist ideology (benevolent, hostile, or control) was manipulated within participants. Women showed less active responses when the partner had been described as a benevolent sexist man. This effect was replicated in Study 2 (n = 103), which showed a relationship between women's less active responses and the belief that benevolent sexist men are very attracted to and interested in their partners. Study 3 (n = 130) demonstrated experimentally that women's responses are less active when they are exposed to information that indicates that the perpetrator is both high in benevolent sexism and highly attracted to his victim than when the latter information is not provided. Results suggest that sexist ideology and particularly benevolent sexism-attributed to the perpetrator in this case-is highly important in women's reactions to acts of sexual violence perpetrated by male intimate partners.


Assuntos
Adaptação Psicológica , Delitos Sexuais/psicologia , Sexismo , Parceiros Sexuais/psicologia , Adolescente , Adulto , Feminino , Humanos , Relações Interpessoais , Adulto Jovem
16.
Hum Mutat ; 34(12): 1615-8, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24027083

RESUMO

Recently, it has been reported that biallelic mutations in the ERCC4 (FANCQ) gene cause Fanconi anemia (FA) subtype FA-Q. To investigate the possible role of ERCC4 in breast and ovarian cancer susceptibility, as occurs with other FA genes, we screened the 11 coding exons and exon-intron boundaries of ERCC4 in 1573 index cases from high-risk Spanish familial breast and ovarian cancer pedigrees that had been tested negative for BRCA1 and BRCA2 mutations and 854 controls. The frequency of ERCC4 mutation carriers does not differ between cases and controls, suggesting that ERCC4 is not a cancer susceptibility gene. Interestingly, the prevalence of ERCC4 mutation carriers (one in 288) is similar to that reported for FANCA, whereas there are approximately 100-fold more FA-A than FA-Q patients, indicating that most biallelic combinations of ERCC4 mutations are embryo lethal. Finally, we identified additional bone-fide FA ERCC4 mutations specifically disrupting interstrand cross-link repair.


Assuntos
Alelos , Neoplasias da Mama/congênito , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Variação Genética , Neoplasias Ovarianas/genética , Substituição de Aminoácidos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Proteínas de Ligação a DNA/metabolismo , Éxons , Feminino , Síndrome Hereditária de Câncer de Mama e Ovário , Heterozigoto , Humanos , Mutação , Neoplasias Ovarianas/metabolismo , Fenótipo , Espanha
17.
Carcinogenesis ; 34(11): 2505-11, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23929434

RESUMO

BRCA2-c.2808_2811del (3036delACAA) is one of the most reported germ line mutations in non-Ashkenazi breast cancer patients. We investigated its genetic origin in 51 Spanish carrier families that were genotyped with 11 13q polymorphic markers. Three independent associated haplotypes were clearly distinguished accounting for 23 [west Castilla y León (WCL)], 20 [east Castilla y León (ECL)] and 6 (South of Spain) families. Mutation age was estimated with the Disequilibrium Mapping using Likelihood Estimation software in a range of 45-68 and 45-71 generations for WCL and ECL haplotypes, respectively. The most prevalent variants, c.2808_2811del and c.2803G > A, were located in a double-hairpin loop structure (c.2794-c.2825) predicted by Quikfold that was proposed as a mutational hotspot. To check this hypothesis, random mutagenesis was performed over a 923 bp fragment of BRCA2, and 86 DNA variants were characterized. Interestingly, three mutations reported in the mutation databases (c.2680G > A, c.2944del and c.2957dup) were replicated and 20 affected the same position with different nucleotide changes. Moreover, five variants were placed in the same hairpin loop of c.2808_2811del, and one affected the same position (c.2808A > G). In conclusion, our results support that at least three different mutational events occurred to generate c.2808_2811del. Other highly prevalent DNA variants, such as BRCA1-c.68_69delAG, BRCA2-c.5946delT and c.8537delAG, are concentrated in hairpin loops, suggesting that these structures may represent mutational hotspots.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Haplótipos/genética , Mutação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Pareamento de Bases , Sequência de Bases , Família , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutagênese , Polimorfismo Genético , Prognóstico , Espanha
18.
Int J Colorectal Dis ; 28(9): 1195-201, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23588873

RESUMO

BACKGROUND: Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by heterozygous mutations in mismatch repair (MMR) genes. Approximately 85 % of genetically defined HNPCC patients have germline mutations in MLH1 and MSH2. HNPCC patients are at increased risk of developing extracolonic cancers. The early age of onset, predominantly right-sided colon cancers, and synchronous and metachronous cancers are other features of the syndrome. HNPCC shows heterogeneous clinical phenotypes, and differences in gene mutation frequencies have been observed in some countries. Several investigators have tried to correlate the phenotype with the affected gene. METHODS: A total of 46 individuals from 22 unrelated families, of the 264 families fulfilling the inclusion criteria, with deleterious mutations in MLH1, MSH2, or MSH6 genes were identified. We evaluated these clinicopathological features in their relation to different genetic parameters (gene mutated, type of mutation, or alteration of the MMR system in high-risk families) in order to establish a relationship between the phenotype and the genotype in our series. RESULTS: The phenotype of the disease seems not to be influenced by the type of mutation, but rather by the mutated gene. The presence of multiple tumors is associated with mutations in the MSH2 gene. The mean age at diagnosis of the first colorectal cancer (CRC) was almost identical in families with mutations in MLH1 and MSH2, about 50 years of age, but this age may increase by almost 10 years for MSH6 mutation carriers. CONCLUSION: The identification of genotype-phenotype correlations could provide a more specific surveillance program focused on the individualized risk.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Reparo de Erro de Pareamento de DNA/genética , Estudos de Associação Genética , Mutação/genética , Adulto , Família , Feminino , Rearranjo Gênico/genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação Puntual/genética
19.
J Mol Diagn ; 15(3): 380-90, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23523604

RESUMO

Lynch syndrome is caused by mutations in one of the mismatch-repair system (MMR) genes. A major difficulty in diagnosis and management of Lynch syndrome is the existence of unclassified genetic variants (UVs) with unknown clinical significance, especially mutations with new descriptions and missense-type nucleotide substitutions. We evaluated the pathogenicity of 20 such mutations (6 in MLH1, 4 in MSH2, and 7 in MSH6) found in Spanish patients suspected of Lynch syndrome. The UVs were tested for evidence of MMR defect in tumor samples and were evaluated for co-occurrence with a pathogenic mutation, the cosegregation of the variant with the disease; where sufficient data were available, in silico resources at the protein level and mRNA analysis were used to assess the putative effect on the splicing mechanism. To evaluate the frequency of these UVs in the general population, a case--control study was also performed. Five variants were identified with similar frequencies in both cases and controls, suggesting a nonpathogenic effect in patients. In contrast, abnormal splicing mutations were detected in a high proportion of patients [3/20 (15%)]. In this study, we classified 15 of the 20 UVs: six variants with strong evidence of pathogenicity and nine variants that should be considered neutral variants. Clinical significance of the other five remains unknown.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Biologia Computacional , Reparo de Erro de Pareamento de DNA , RNA/isolamento & purificação , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Estudos de Casos e Controles , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/genética , Mutação de Sentido Incorreto , Proteínas Nucleares/genética , Fenótipo , RNA/genética , Processamento de RNA , Espanha
20.
PLoS One ; 8(2): e55681, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23409019

RESUMO

The identification of the two most prevalent susceptibility genes in breast cancer, BRCA1 and BRCA2, was the beginning of a sustained effort to uncover new genes explaining the missing heritability in this disease. Today, additional high, moderate and low penetrance genes have been identified in breast cancer, such as P53, PTEN, STK11, PALB2 or ATM, globally accounting for around 35 percent of the familial cases. In the present study we used massively parallel sequencing to analyze 7 BRCA1/BRCA2 negative families, each having at least 6 affected women with breast cancer (between 6 and 10) diagnosed under the age of 60 across generations. After extensive filtering, Sanger sequencing validation and co-segregation studies, variants were prioritized through either control-population studies, including up to 750 healthy individuals, or case-control assays comprising approximately 5300 samples. As a result, a known moderate susceptibility indel variant (CHEK2 1100delC) and a catalogue of 11 rare variants presenting signs of association with breast cancer were identified. All the affected genes are involved in important cellular mechanisms like DNA repair, cell proliferation and survival or cell cycle regulation. This study highlights the need to investigate the role of rare variants in familial cancer development by means of novel high throughput analysis strategies optimized for genetically heterogeneous scenarios. Even considering the intrinsic limitations of exome resequencing studies, our findings support the hypothesis that the majority of non-BRCA1/BRCA2 breast cancer families might be explained by the action of moderate and/or low penetrance susceptibility alleles.


Assuntos
Alelos , Neoplasias da Mama/genética , Exoma , Genes BRCA1 , Genes BRCA2 , Feminino , Humanos
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