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1.
Endocr Relat Cancer ; 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31476737

RESUMO

The first study establishing exposure to ionizing radiations (IR) as a risk factor for differentiated thyroid cancer (DTC) was published 70 years ago. Given that radiation exposure causes direct DNA damage, genetic alterations in the different DNA repair mechanisms are assumed to play an important role in long-term IR induced DNA damage prevention. Individual variations in DNA repair capacity may cause different reaction to damage made by IR exposure. The aim of this review is to recapitulate current knowledge about constitutional genetic polymorphisms found to be significatively associated with DTC occurring after IR exposure. Studies were screened online using electronic databases, only fully available articles, studies performed among irradiated population or taking radiation exposure as adjustment factors and showing significative results are included. Nine articles were identified. Ten variants in/near to genes in six biological pathways, namely thyroid activity regulations, generic transcription, RET signaling, ATM signaling and DNA repair pathways were found to be associated with radiation-related DTC in these studies. Only seven variants were found to be in interaction with IR exposure in DTC risk. Most of these variants are also associated to sporadic DTC and are not specific to IR related DTC. In the published studies, no data on children treated with radiotherapy is described. In conclusion, more studies carried out on larger cohorts or on case-control studies with well documented individual radiation dose estimations are needed to get a comprehensive picture of genetic susceptibility factors involved in radiation-related DTC.

2.
Autism Res ; 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31373761

RESUMO

A growing body of evidence suggests that children of immigrants may have increased risks of neurodevelopmental disorders. However, evidence based on parent report and on very young children is lacking. We therefore investigated the association between maternal immigrant status and early signs of neurodevelopmental problems in a population-based sample of 2-year-old children using standardized parent-report instruments. We used data from the French representative Étude Longitudinale Française depuis l'Enfance birth cohort, initiated in 2011. The study sample included 9,900 children of nonimmigrant French, 1,403 children of second, and 1,171 children of first generation immigrant women followed-up to age 2 years. Neurodevelopment was assessed using the Modified Checklist for Autism in Toddlers (M-CHAT) and an adaptation of the MacArthur-Bates Communicative Development Inventories (MB-CDI). In fully adjusted linear regression models, maternal immigrant status was associated with M-CHAT scores, with stronger associations in children of first (ß-coefficient: 0.19; 95% CI 0.08-0.29) than second generation immigrants (0.09; 0.01-0.17). This association was especially strong among children of first generation immigrant mothers native of North Africa (vs. nonimmigrant French: 0.33; 0.16-0.49) and French-speaking Sub-Saharan Africa (0.26; 0.07-0.45). MB-CDI scores were lowest among children of first generation immigrant mothers, particularly from mostly non-francophone regions. Children of first generation immigrant mothers were most likely to have simultaneously low MB-CDI and high M-CHAT scores. Our findings suggest that maternal immigrant status is associated with early signs of neurodevelopmental difficulties, with strong variations according to maternal region of origin. Further research is necessary to test whether these associations persist and to determine the underlying mechanisms. Autism Res 2019. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We asked immigrant and nonimmigrant mothers in France about early signs of neurodevelopmental problems in their 2-year-old children. Overall, we found that children of immigrants may be at higher risk of showing these early warning signs, as compared to children of nonimmigrants. This is in line with previous studies, which were based on doctors' diagnoses at later ages. However, our results differed depending on the mothers' regions of origin. We found the highest risks in children of first generation immigrants from North and French-speaking Sub-Saharan Africa, who also seemed especially at risk of neurodevelopmental problems combined with low language development.

3.
Hum Mutat ; 40(10): 1781-1796, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31112363

RESUMO

BRCA1 and BRCA2 (BRCA1/2) pathogenic sequence variants (PSVs) confer elevated risks of multiple cancers. However, most BRCA1/2 PSVs reports focus on European ancestry individuals. Knowledge of the PSV distribution in African descent individuals is poorly understood. We undertook a systematic review of the published literature and publicly available databases reporting BRCA1/2 PSVs also accessed the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) database to identify African or African descent individuals. Using these data, we inferred which of the BRCA PSVs were likely to be of African continental origin. Of the 43,817 BRCA1/2 PSV carriers in the CIMBA database, 469 (1%) were of African descent. Additional African descent individuals were identified in public databases (n = 291) and the literature (n = 601). We identified 164 unique BRCA1 and 173 unique BRCA2 PSVs in individuals of African ancestry. Of these, 83 BRCA1 and 91 BRCA2 PSVs are of likely or possible African origin. We observed numerous differences in the distribution of PSV type and function in African origin versus non-African origin PSVs. Research in populations of African ancestry with BRCA1/2 PSVs is needed to provide the information needed for clinical management and decision-making in African descent individuals worldwide.

4.
Leuk Lymphoma ; 60(7): 1803-1811, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30633655

RESUMO

Genetic variants in genes acting during the maturation process of immature B-cell to differentiated plasma cell could influence the risk of developing multiple myeloma (MM). During B-cell maturation, several programmed genetic rearrangements occur to increase the variation of the immunoglobulin chains. Class switch recombination (CSR) is one of the most important among these mechanisms. Germline polymorphisms altering even subtly this process could play a role in the etiology and outcome of MM. We performed an association study of 30 genetic variants in the key CSR genes, using 2632 MM patients and 2848 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the Heidelberg MM Group and the ESTHER cohort. We found an association between LIG4-rs1555902 and decreased MM risk, which approached statistical significance, as well as significant associations between AICDA-rs3794318 and better outcome. Our results add to our knowledge on the genetic component of MM risk and survival.

5.
Tob Control ; 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30409812

RESUMO

BACKGROUND: Plain packaging (PP) of tobacco products and increased graphic warnings may contribute to lower attractiveness of smoking, particularly among youths. In France, this policy was introduced on 1 January 2017. We examined changes in smoking-related perceptions and behaviours among a nationwide sample of French adolescents before (2016) and 1 year post (2017) implementation. METHODS: DePICT is a two-wave cross-sectional national telephone survey of adolescents aged 12-17 years per study wave (2016: n=2046 2017: n=1999). All participants reported smoking-related perceptions, as well as ever and current tobacco use. Smokers were also asked about their perceptions of tobacco brands. Data were weighted to be representative of youths in the French population: adjusted prevalence ratios (PRs, 95% CI) estimating changes between the two study waves were calculated using multivariate log-binomial regression models. RESULTS: In 2017, as compared with 2016, French adolescents were more likely to report fear of the consequences of smoking (PR=1.06, 95% CI 1.02 to 1.09) and that smoking is dangerous (PR=1.08, 95% CI 1.05 to 1.11). They were also less likely to report that their friends (PR=0.61, 95% CI 0.54 to 0.70) and family (PR=0.51, 95% CI 0.44 to 0.60) accept smoking. Additionally, smoking initiation significantly decreased (PR=0.96, 95% CI 0.93 to 0.98) and a non-statistically significant drop in current tobacco use was observed (PR=0.93, 95% CI 0.78 to 1.11). Smokers' attachment to their tobacco brand also decreased (PR=0.47, 95% CI 0.30 to 0.73). CONCLUSION: Our findings suggest that PP and increased graphic warnings could contribute to changes in smoking norms and rates among adolescents.

7.
BMJ ; 362: k3631, 2018 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-30232118
8.
Int J Public Health ; 63(9): 1027-1036, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30097678

RESUMO

OBJECTIVES: Despite the healthy migrant effect, immigrants and descendants of immigrants face health challenges and socio-economic difficulties. The objective of this study is to examine the perinatal health of women of migrant origin. METHODS: The nationwide French ELFE (Etude Longitudinale Française Depuis l'Enfance) birth cohort study recruited approximately 18,000 women. We studied pre-pregnancy BMI, gestational diabetes mellitus (GDM), as well as tobacco, and alcohol consumption during pregnancy according to migrant status and region of origin. RESULTS: Women from North Africa and Turkey had a higher risk of pre-pregnancy overweight and GDM, while women from Eastern Europe and Asia had a lower risk of pre-pregnancy overweight and obesity, but a higher risk of GDM compared to non-immigrants. Women from Sub-Saharan Africa had a higher risk of being overweight or obese pre-pregnancy. Compared to non-immigrants, immigrants-but not descendants of immigrants-had lower levels of tobacco smoking, while descendants of immigrants were less likely to drink alcohol during pregnancy. CONCLUSIONS: Pregnant women of migrant origin have particular health needs and should benefit from a medical follow-up which addresses those needs.

9.
Breast Cancer Res ; 20(1): 28, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29665859

RESUMO

BACKGROUND: The ataxia telangiectasia mutated (ATM) gene is a moderate-risk breast cancer susceptibility gene; germline loss-of-function variants are found in up to 3% of hereditary breast and ovarian cancer (HBOC) families who undergo genetic testing. So far, no clear histopathological and molecular features of breast tumours occurring in ATM deleterious variant carriers have been described, but identification of an ATM-associated tumour signature may help in patient management. METHODS: To characterise hallmarks of ATM-associated tumours, we performed systematic pathology review of tumours from 21 participants from ataxia-telangiectasia families and 18 participants from HBOC families, as well as copy number profiling on a subset of 23 tumours. Morphology of ATM-associated tumours was compared with that of 599 patients with no BRCA1 and BRCA2 mutations from a hospital-based series, as well as with data from The Cancer Genome Atlas. Absolute copy number and loss of heterozygosity (LOH) profiles were obtained from the OncoScan SNP array. In addition, we performed whole-genome sequencing on four tumours from ATM loss-of-function variant carriers with available frozen material. RESULTS: We found that ATM-associated tumours belong mostly to the luminal B subtype, are tetraploid and show LOH at the ATM locus at 11q22-23. Unlike tumours in which BRCA1 or BRCA2 is inactivated, tumours arising in ATM deleterious variant carriers are not associated with increased large-scale genomic instability as measured by the large-scale state transitions signature. Losses at 13q14.11-q14.3, 17p13.2-p12, 21p11.2-p11.1 and 22q11.23 were observed. Somatic alterations at these loci may therefore represent biomarkers for ATM testing and harbour driver mutations in potentially 'druggable' genes that would allow patients to be directed towards tailored therapeutic strategies. CONCLUSIONS: Although ATM is involved in the DNA damage response, ATM-associated tumours are distinct from BRCA1-associated tumours in terms of morphological characteristics and genomic alterations, and they are also distinguishable from sporadic breast tumours, thus opening up the possibility to identify ATM variant carriers outside the ataxia-telangiectasia disorder and direct them towards effective cancer risk management and therapeutic strategies.

10.
Addict Behav ; 80: 110-115, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29407680

RESUMO

INTRODUCTION: A substantial proportion of smokers who attempt to stop smoking relapse in the first months. Yet to date, there is limited understanding of the predictors of smoking attempts and their success. We examine the role of tobacco use characteristics, other substance-related factors, as well as socio-demographic characteristics in relation to successful and unsuccessful smoking cessation. METHODS: DePICT (Description des Perceptions, Images, et Comportements liés au Tabagisme) is a nationally representative sample of adults aged between 18 and 64years residing in metropolitan France, who were interviewed by telephone survey (n=4342). Among current or former smokers (n=2110) we distinguished participants characterized by: a) no quit attempt or quit <6months; b) unsuccessful smoking cessation (current smokers who previously quit smoking ≥6months); c) successful smoking cessation (≥6months). Factors associated with successful vs. unsuccessful smoking cessation were studied using multivariate multinomial logistic regression analyses. RESULTS: Successful and unsuccessful smoking cessation share some predicting factors including no cannabis use, older age, and intermediate or high occupational grade. Factors specifically associated with successful smoking cessation included no e-cigarette use, no environmental tobacco exposure, fear of the health consequences of smoking, perceived harmfulness of smoking, and high educational attainment and a good overall health. CONCLUSIONS: Smokers' environmental tobacco exposure, concurrent cannabis use, and the perception of the health consequences of smoking should be taken into account in efforts aiming to promote smoking cessation at the individual as well as collective levels. Our data also suggest that e-cigarette use is associated with unsuccessful rather than successful smoking cessation, which should be verified in additional, longitudinal, studies.

11.
Carcinogenesis ; 38(10): 994-1003, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28981872

RESUMO

Recent studies have linked constitutive telomere length (TL) to aging-related diseases including cancer at different sites. ATM participates in the signaling of telomere erosion, and inherited mutations in ATM have been associated with increased risk of cancer, particularly breast cancer. The goal of this study was to investigate whether carriage of an ATM mutation and TL interplay to modify cancer risk in ataxia-telangiectasia (A-T) families.The study population consisted of 284 heterozygous ATM mutation carriers (HetAT) and 174 non-carriers (non-HetAT) from 103 A-T families. Forty-eight HetAT and 14 non-HetAT individuals had cancer, among them 25 HetAT and 6 non-HetAT were diagnosed after blood sample collection. We measured mean TL using a quantitative PCR assay and genotyped seven single-nucleotide polymorphisms (SNPs) recurrently associated with TL in large population-based studies.HetAT individuals were at increased risk of cancer (OR = 2.3, 95%CI = 1.2-4.4, P = 0.01), and particularly of breast cancer for women (OR = 2.9, 95%CI = 1.2-7.1, P = 0.02), in comparison to their non-HetAT relatives. HetAT individuals had longer telomeres than non-HetAT individuals (P = 0.0008) but TL was not associated with cancer risk, and no significant interaction was observed between ATM mutation status and TL. Furthermore, rs9257445 (ZNF311) was associated with TL in HetAT subjects and rs6060627 (BCL2L1) modified cancer risk in HetAT and non-HetAT women.Our findings suggest that carriage of an ATM mutation impacts on the age-related TL shortening and that TL per se is not related to cancer risk in ATM carriers. TL measurement alone is not a good marker for predicting cancer risk in A-T families.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/complicações , Mutação , Neoplasias/genética , Telômero/genética , Ataxia Telangiectasia/genética , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Encurtamento do Telômero/genética , Proteína bcl-X/genética
12.
BMC Cancer ; 17(1): 328, 2017 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-28499365

RESUMO

BACKGROUND: Genetic factors may influence an individual's sensitivity to ionising radiation and therefore modify his/her risk of developing papillary thyroid carcinoma (PTC). Previously, we reported that common single nucleotide polymorphisms (SNPs) within the DNA damage recognition gene ATM contribute to PTC risk in Belarusian children exposed to fallout from the Chernobyl power plant accident. Here we explored in the same population the contribution of a panel of DNA repair-related SNPs in genes acting downstream of ATM. METHODS: The association of 141 SNPs located in 43 DNA repair genes was examined in 75 PTC cases and 254 controls from the Gomel region in Belarus. All subjects were younger than 15 years at the time of the Chernobyl accident. Conditional logistic regressions accounting for radiation dose were performed with PLINK using the additive allelic inheritance model, and a linkage disequilibrium (LD)-based Bonferroni correction was used for correction for multiple testing. RESULTS: The intronic SNP rs2296675 in MGMT was associated with an increased PTC risk [per minor allele odds ratio (OR) 2.54 95% CI 1.50, 4.30, P per allele = 0.0006, P corr.= 0.05], and gene-wide association testing highlighted a possible role for ERCC5 (P Gene = 0.01) and PCNA (P Gene = 0.05) in addition to MGMT (P Gene = 0.008). CONCLUSIONS: These findings indicate that several genes acting in distinct DNA repair mechanisms contribute to PTC risk. Further investigation is needed to decipher the functional properties of the methyltransferase encoded by MGMT and to understand how alteration of such functions may lead to the development of the most common type of thyroid cancer.


Assuntos
Carcinoma Papilar/genética , Acidente Nuclear de Chernobyl , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Reparo do DNA/genética , Neoplasias Induzidas por Radiação/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Glândula Tireoide/genética , Proteínas Supressoras de Tumor/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Estudos de Casos e Controles , Exposição Ambiental/efeitos adversos , Feminino , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação/genética , Masculino , Radiação Ionizante , República de Belarus , Câncer Papilífero da Tireoide
13.
Int J Cancer ; 140(3): 526-534, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27718532

RESUMO

Multiple myeloma (MM) is a malignancy of plasma cells usually infiltrating the bone marrow, associated with the production of a monoclonal immunoglobulin (M protein) which can be detected in the blood and/or urine. Multiple lines of evidence suggest that genetic factors are involved in MM pathogenesis, and several studies have identified single nucleotide polymorphisms (SNPs) associated with the susceptibility to the disease. SNPs within miRNA-binding sites in target genes (miRSNPs) may alter the strength of miRNA-mRNA interactions, thus deregulating protein expression. MiRSNPs are known to be associated with risk of various types of cancer, but they have never been investigated in MM. We performed an in silico genome-wide search for miRSNPs predicted to alter binding of miRNAs to their target sequences. We selected 12 miRSNPs and tested their association with MM risk. Our study population consisted of 1,832 controls and 2,894 MM cases recruited from seven European countries and Israel in the context of the IMMEnSE (International Multiple Myeloma rESEarch) consortium. In this population two SNPs showed an association with p < 0.05: rs286595 (located in gene MRLP22) and rs14191881 (located in gene TCF19). Results from IMMEnSE were meta-analyzed with data from a previously published genome-wide association study (GWAS). The SNPs rs13409 (located in the 3'UTR of the POU5F1 gene), rs1419881 (TCF19), rs1049633, rs1049623 (both in DDR1) showed significant associations with MM risk. In conclusion, we sought to identify genetic polymorphisms associated with MM risk starting from genome-wide prediction of miRSNPs. For some mirSNPs, we have shown promising associations with MM risk.


Assuntos
Predisposição Genética para Doença/genética , MicroRNAs/genética , Mieloma Múltiplo/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões 3' não Traduzidas/genética , Adulto , Idoso , Sítios de Ligação/genética , Estudos de Casos e Controles , Europa (Continente) , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Mieloma/genética , RNA Mensageiro/genética , Risco
14.
Thyroid ; 26(12): 1752-1760, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27610545

RESUMO

BACKGROUND: The incidence of differentiated thyroid cancer (DTC) is low in Cuba, and the contribution of dietary factors to DTC in this population has not been investigated so far. The aim of this study was to evaluate the relationship between dietary iodine intake and DTC with regard to the interaction with environmental factors or some common single nucleotide polymorphisms (SNPs), based on a case-control study carried out in Cuba. METHODS: A total of 203 cases and 212 controls from the general population were interviewed face-to-face using the dietary intake questionnaire and the photo booklet from the E3N cohort. A specific food composition table was constructed for this study. For each parameter studied, the odds ratio (OR) was stratified on age group and sex, and further adjusted for dietary energy, smoking status, ethnic group, level of education, number of pregnancies, and body surface area. RESULTS: The risk of DTC was significantly reduced with increasing consumption of fish (p = 0.04), but no association between total dietary iodine intake and DTC risk was evident (p = 0.7). This lack of significant association was true whatever the age, the smoking status, the dietary selenium intake, and the ethnicity (p > 0.05). DTC risk was positively and strongly associated with the number of copies in the minor allele (A) for SNP rs965513 near FOXE1 among people who consumed less iodine than the median (p = 0.005). CONCLUSION: Overall, the majority of the studied population had an optimal dietary iodine intake. DTC risk was inversely associated with high fish consumption. Furthermore, DTC risk was positively associated with the number of copies in the minor allele (A) of rs965513 among people who consumed less iodine than the median. Because these findings are based on post-diagnostic measures, studies with pre-diagnostic dietary iodine are needed for confirmation.


Assuntos
Dieta , Fatores de Transcrição Forkhead/genética , Interação Gene-Ambiente , Iodo/administração & dosagem , Polimorfismo de Nucleotídeo Único , Neoplasias da Glândula Tireoide/etiologia , Adolescente , Adulto , Alelos , Estudos de Casos e Controles , Cuba , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Risco , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Adulto Jovem
15.
Oncotarget ; 7(37): 59029-59048, 2016 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-27437873

RESUMO

Diabetogenic single nucleotide polymorphisms (SNPs) have recently been associated with multiple myeloma (MM) risk but their impact on overall survival (OS) of MM patients has not been analysed yet. In order to investigate the impact of 58 GWAS-identified variants for type 2 diabetes (T2D) on OS of patients with MM, we analysed genotyping data of 936 MM patients collected by the International Multiple Myeloma rESEarch (IMMENSE) consortium and an independent set of 700 MM patients recruited by the University Clinic of Heidelberg. A meta-analysis of the cox regression results of the two sets showed that rs7501939 located in the HNF1B gene negatively impacted OS (HRRec= 1.44, 95% CI = 1.18-1.76, P = 0.0001). The meta-analysis also showed a noteworthy gender-specific association of the SLC30A8rs13266634 SNP with OS. The presence of each additional copy of the minor allele at rs13266634 was associated with poor OS in men whereas no association was seen in women (HRMen-Add = 1.32, 95% CI 1.13-1.54, P = 0.0003). In conclusion, these data suggest that the HNF1Brs7501939 SNP confers poor OS in patients with MM and that a SNP in SLC30A8 affect OS in men.


Assuntos
Diabetes Mellitus Tipo 2/genética , Genótipo , Fator 1-beta Nuclear de Hepatócito/genética , Mieloma Múltiplo/genética , Fatores Sexuais , Transportador 8 de Zinco/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Mieloma Múltiplo/mortalidade , Polimorfismo de Nucleotídeo Único , Análise de Sobrevida
16.
PLoS One ; 11(6): e0156820, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27270457

RESUMO

Approximately half of the familial aggregation of breast cancer remains unexplained. This proportion is less for early-onset disease where familial aggregation is greater, suggesting that other susceptibility genes remain to be discovered. The majority of known breast cancer susceptibility genes are involved in the DNA double-strand break repair pathway. ABRAXAS is involved in this pathway and mutations in this gene impair BRCA1 recruitment to DNA damage foci and increase cell sensitivity to ionizing radiation. Moreover, a recurrent germline mutation was reported in Finnish high-risk breast cancer families. To determine if ABRAXAS could be a breast cancer susceptibility gene in other populations, we conducted a population-based case-control mutation screening study of the coding exons and exon/intron boundaries of ABRAXAS in the Breast Cancer Family Registry. In addition to the common variant p.Asp373Asn, sixteen distinct rare variants were identified. Although no significant difference in allele frequencies between cases and controls was observed for the identified variants, two variants, p.Gly39Val and p.Thr141Ile, were shown to diminish phosphorylation of gamma-H2AX in MCF7 human breast adenocarcinoma cells, an important biomarker of DNA double-strand breaks. Overall, likely damaging or neutral variants were evenly represented among cases and controls suggesting that rare variants in ABRAXAS may explain only a small proportion of hereditary breast cancer.


Assuntos
Neoplasias da Mama/genética , Proteínas de Transporte/genética , Estudos de Associação Genética/métodos , Polimorfismo de Nucleotídeo Único , Idade de Início , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Células MCF-7 , Linhagem , Quebeque
17.
Int J Cancer ; 139(3): 617-27, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-26991144

RESUMO

Incidence of differentiated thyroid carcinoma varies considerably between countries and ethnic groups, with particularly high incidence rates in Melanesians of New Caledonia. Differentiated thyroid cancer (DTC) has a familial relative risk higher than other cancers, highlighting the contribution of inherited factors to the disease. Recently, genome-wide association studies (GWAS) identified several DTC susceptibility loci. The most robust associations were reported at loci 9q22 (rs965513 and rs1867277) and 14q13 (rs944289 and rs116909734). In this study, we performed a fine-mapping study of the two gene regions among Europeans and Melanesians from Metropolitan France and New Caledonia. We examined 81 single nucleotide polymorphisms (SNPs) at 9q22 and 561 SNPs at 14q13 in Europeans (625 cases/776 controls) and in Melanesians (244 cases/189 controls). The association with the four SNPs previously identified in GWAS was replicated in Europeans while only rs944289 was replicated in Melanesians. Among Europeans, we found that the two SNPs previously reported at 9q22 were not independently associated to DTC and that rs965513 was the predominant signal; at 14q13, we showed that the haplotype rs944289[C]-rs116909374[C]-rs999460[T] was significantly associated with DTC risk and that the association with rs116909374 differed by smoking status (p-interaction = 0.03). Among Melanesians, a new independent signal was observed at 14q13 for rs1755774 which is strongly correlated to rs2787423; this latter is potentially a functional variant. Significant interactions with parity (p < 0.05) and body mass index were observed for rs1755774 and rs2787423. This study contributed to a better characterization of the DTC loci 9q22 and 14q13 in Europeans and in Melanesians and has identified novel variants to be prioritized for further functional studies.


Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 9 , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Biologia Computacional/métodos , Feminino , França , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Melanesia , Pessoa de Meia-Idade , Nova Caledônia , Razão de Chances , Vigilância da População , Fatores de Risco , Neoplasias da Glândula Tireoide/epidemiologia
18.
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
20.
Endocr Relat Cancer ; 22(4): 545-59, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26099684

RESUMO

Type 2 diabetes (T2D) has been suggested to be a risk factor for multiple myeloma (MM), but the relationship between the two traits is still not well understood. The aims of this study were to evaluate whether 58 genome-wide-association-studies (GWAS)-identified common variants for T2D influence the risk of developing MM and to determine whether predictive models built with these variants might help to predict the disease risk. We conducted a case-control study including 1420 MM patients and 1858 controls ascertained through the International Multiple Myeloma (IMMEnSE) consortium. Subjects carrying the KCNQ1rs2237892T allele or the CDKN2A-2Brs2383208G/G, IGF1rs35767T/T and MADDrs7944584T/T genotypes had a significantly increased risk of MM (odds ratio (OR)=1.32-2.13) whereas those carrying the KCNJ11rs5215C, KCNJ11rs5219T and THADArs7578597C alleles or the FTOrs8050136A/A and LTArs1041981C/C genotypes showed a significantly decreased risk of developing the disease (OR=0.76-0.85). Interestingly, a prediction model including those T2D-related variants associated with the risk of MM showed a significantly improved discriminatory ability to predict the disease when compared to a model without genetic information (area under the curve (AUC)=0.645 vs AUC=0.629; P=4.05×10(-) (06)). A gender-stratified analysis also revealed a significant gender effect modification for ADAM30rs2641348 and NOTCH2rs10923931 variants (Pinteraction=0.001 and 0.0004, respectively). Men carrying the ADAM30rs2641348C and NOTCH2rs10923931T alleles had a significantly decreased risk of MM whereas an opposite but not significant effect was observed in women (ORM=0.71 and ORM=0.66 vs ORW=1.22 and ORW=1.15, respectively). These results suggest that TD2-related variants may influence the risk of developing MM and their genotyping might help to improve MM risk prediction models.


Assuntos
Diabetes Mellitus Tipo 2/genética , Mieloma Múltiplo/genética , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Modelos Genéticos , Mieloma Múltiplo/epidemiologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco
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