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1.
Blood ; 123(16): 2513-7; quiz 2593, 2014 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-24449210

RESUMO

Monoclonal gammopathy of undetermined significance (MGUS) is present in ∼2% of individuals age >50 years. The increased risk of multiple myeloma (MM) in relatives of individuals with MGUS is consistent with MGUS being a marker of inherited genetic susceptibility to MM. Common single-nucleotide polymorphisms (SNPs) at 2p23.3 (rs6746082), 3p22.1 (rs1052501), 3q26.2 (rs10936599), 6p21.33 (rs2285803), 7p15.3 (rs4487645), 17p11.2 (rs4273077), and 22q13.1 (rs877529) have recently been shown to influence MM risk. To examine the impact of these 7 SNPs on MGUS, we analyzed two case-control series totaling 492 cases and 7306 controls. Each SNP independently influenced MGUS risk with statistically significant associations (P < .02) for rs1052501, rs2285803, rs4487645, and rs4273077. SNP associations were independent, with risk increasing with a larger number of risk alleles carried (per allele odds ratio, 1.18; P < 10(-7)). Collectively these data are consistent with a polygenic model of disease susceptibility to MGUS.


Assuntos
Gamopatia Monoclonal de Significância Indeterminada/genética , Mieloma Múltiplo/genética , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/epidemiologia , Gamopatia Monoclonal de Significância Indeterminada/patologia , Mieloma Múltiplo/epidemiologia , Polimorfismo de Nucleotídeo Único
2.
Blood ; 122(19): 3298-307, 2013 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-23996088

RESUMO

Acute lymphoblastic leukemia (ALL) is the major pediatric cancer diagnosed in economically developed countries with B-cell precursor (BCP)-ALL, accounting for approximately 70% of ALL. Recent genome-wide association studies (GWAS) have provided the first unambiguous evidence for common inherited susceptibility to BCP-ALL, identifying susceptibility loci at 7p12.2, 9p21.3, 10q21.2, and 14q11.2. To identify additional BCP-ALL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1658 cases and 4723 controls, with validation in 1449 cases and 1488 controls. Combined analysis identified novel loci mapping to 10p12.2 (rs10828317, odds ratio [OR] = 1.23; P = 2.30 × 10(-9)) and 10p14 marked by rs3824662 (OR = 1.31; P = 8.62 × 10(-12)). The single nucleotide polymorphism rs10828317 is responsible for the N215S polymorphism in exon 7 of PIP4K2A, and rs3824662 localizes to intron 3 of the transcription factor and putative tumor suppressor gene GATA3. The rs10828317 association was shown to be specifically associated with hyperdiploid ALL, whereas the rs3824662-associated risk was confined to nonhyperdiploid non-TEL-AML1 + ALL. The risk allele of rs3824662 was correlated with older age at diagnosis (P < .001) and significantly worse event-free survivorship (P < .0001). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to BCP-ALL and the influence of constitutional genotype on disease development.


Assuntos
Cromossomos Humanos Par 10 , Fator de Transcrição GATA3/genética , Fenótipo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Fatores Etários , Alelos , Linfócitos B/metabolismo , Linfócitos B/patologia , Criança , Éxons , Feminino , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Análise de Sobrevida
3.
Nat Genet ; 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39284974

RESUMO

Genome-wide association studies of colorectal cancer (CRC) have identified 170 autosomal risk loci. However, for most of these, the functional variants and their target genes are unknown. Here, we perform statistical fine-mapping incorporating tissue-specific epigenetic annotations and massively parallel reporter assays to systematically prioritize functional variants for each CRC risk locus. We identify plausible causal variants for the 170 risk loci, with a single variant for 40. We link these variants to 208 target genes by analyzing colon-specific quantitative trait loci and implementing the activity-by-contact model, which integrates epigenomic features and Micro-C data, to predict enhancer-gene connections. By deciphering CRC risk loci, we identify direct links between risk variants and target genes, providing further insight into the molecular basis of CRC susceptibility and highlighting potential pharmaceutical targets for prevention and treatment.

4.
Nat Commun ; 15(1): 2637, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38527997

RESUMO

For many cancers there are only a few well-established risk factors. Here, we use summary data from genome-wide association studies (GWAS) in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to identify potentially causal relationships for over 3,000 traits. Our outcome datasets comprise 378,142 cases across breast, prostate, colorectal, lung, endometrial, oesophageal, renal, and ovarian cancers, as well as 485,715 controls. We complement this analysis by systematically mining the literature space for supporting evidence. In addition to providing supporting evidence for well-established risk factors (smoking, alcohol, obesity, lack of physical activity), we also find sex steroid hormones, plasma lipids, and telomere length as determinants of cancer risk. A number of the molecular factors we identify may prove to be potential biomarkers. Our analysis, which highlights aetiological similarities and differences in common cancers, should aid public health prevention strategies to reduce cancer burden. We provide a R/Shiny app to visualise findings.


Assuntos
Estudo de Associação Genômica Ampla , Neoplasias Ovarianas , Masculino , Feminino , Humanos , Fatores de Risco , Fenômica , Fenótipo , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único
5.
PLoS Genet ; 6(9): e1001126, 2010 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-20862326

RESUMO

Common genetic variation at human 8q23.3 is significantly associated with colorectal cancer (CRC) risk. To elucidate the basis of this association we compared the frequency of common variants at 8q23.3 in 1,964 CRC cases and 2,081 healthy controls. Reporter gene studies showed that the single nucleotide polymorphism rs16888589 acts as an allele-specific transcriptional repressor. Chromosome conformation capture (3C) analysis demonstrated that the genomic region harboring rs16888589 interacts with the promoter of gene for eukaryotic translation initiation factor 3, subunit H (EIF3H). We show that increased expression of EIF3H gene increases CRC growth and invasiveness thereby providing a biological mechanism for the 8q23.3 association. These data provide evidence for a functional basis for the non-coding risk variant rs16888589 at 8q23.3 and provides novel insight into the etiological basis of CRC.


Assuntos
Alelos , Cromossomos Humanos Par 8/genética , Neoplasias Colorretais/genética , Fator de Iniciação 3 em Eucariotos/genética , Predisposição Genética para Doença , Variação Genética , Sequências Reguladoras de Ácido Nucleico/genética , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/patologia , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Reporter/genética , Loci Gênicos/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Ligação Proteica , Fatores de Risco
6.
medRxiv ; 2023 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-37066289

RESUMO

For many cancers there are few well-established risk factors. Summary data from genome-wide association studies (GWAS) can be used in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to identify causal relationships. We performed a MR-PheWAS of breast, prostate, colorectal, lung, endometrial, oesophageal, renal, and ovarian cancers, comprising 378,142 cases and 485,715 controls. To derive a more comprehensive insight into disease aetiology we systematically mined the literature space for supporting evidence. We evaluated causal relationships for over 3,000 potential risk factors. In addition to identifying well-established risk factors (smoking, alcohol, obesity, lack of physical activity), we provide evidence for specific factors, including dietary intake, sex steroid hormones, plasma lipids and telomere length as determinants of cancer risk. We also implicate molecular factors including plasma levels of IL-18, LAG-3, IGF-1, CT-1, and PRDX1 as risk factors. Our analyses highlight the importance of risk factors that are common to many cancer types but also reveal aetiological differences. A number of the molecular factors we identify have the potential to be biomarkers. Our findings should aid public health prevention strategies to reduce cancer burden. We provide a R/Shiny app (https://mrcancer.shinyapps.io/mrcan/) to visualise findings.

7.
Res Sq ; 2023 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-36993383

RESUMO

For many cancers there are few well-established risk factors. Summary data from genome-wide association studies (GWAS) can be used in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to identify causal relationships. We performed a MR-PheWAS of breast, prostate, colorectal, lung, endometrial, oesophageal, renal, and ovarian cancers, comprising 378,142 cases and 485,715 controls. To derive a more comprehensive insight into disease aetiology we systematically mined the literature space for supporting evidence. We evaluated causal relationships for over 3,000 potential risk factors. In addition to identifying well-established risk factors (smoking, alcohol, obesity, lack of physical activity), we provide evidence for specific factors, including dietary intake, sex steroid hormones, plasma lipids and telomere length as determinants of cancer risk. We also implicate molecular factors including plasma levels of IL-18, LAG-3, IGF-1, CT-1, and PRDX1 as risk factors. Our analyses highlight the importance of risk factors that are common to many cancer types but also reveal aetiological differences. A number of the molecular factors we identify have the potential to be biomarkers. Our findings should aid public health prevention strategies to reduce cancer burden. We provide a R/Shiny app (https://mrcancer.shinyapps.io/mrcan/) to visualise findings.

8.
J Exp Clin Cancer Res ; 42(1): 21, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36639636

RESUMO

BACKGROUND: Characterization of clinical phenotypes in context with tumor and host genomic information can aid in the development of more effective and less toxic risk-adapted and targeted treatment strategies. To analyze the impact of therapy-related hyperbilirubinemia on treatment outcome and to identify contributing genetic risk factors of this well-recognized adverse effect we evaluated serum bilirubin levels in 1547 pediatric patients with acute lymphoblastic leukemia (ALL) and conducted a genome-wide association study (GWAS). PATIENTS AND METHODS: Patients were treated in multicenter trial AIEOP-BFM ALL 2000 for pediatric ALL. Bilirubin toxicity was graded 0 to 4 according to the Common Toxicity Criteria (CTC) of the National Cancer Institute. In the GWAS discovery cohort, including 650 of the 1547 individuals, genotype frequencies of 745,895 single nucleotide variants were compared between 435 patients with hyperbilirubinemia (CTC grades 1-4) during induction/consolidation treatment and 215 patients without it (grade 0). Replication analyses included 224 patients from the same trial. RESULTS: Compared to patients with no (grade 0) or moderate hyperbilirubinemia (grades 1-2) during induction/consolidation, patients with grades 3-4 had a poorer 5-year event free survival (76.6 ± 3% versus 87.7 ± 1% for grades 1-2, P = 0.003; 85.2 ± 2% for grade 0, P < 0.001) and a higher cumulative incidence of relapse (15.6 ± 3% versus 9.0 ± 1% for grades 1-2, P = 0.08; 11.1 ± 1% for grade 0, P = 0.007). GWAS identified a strong association of the rs6744284 variant T allele in the UGT1A gene cluster with risk of hyperbilirubinemia (allelic odds ratio (OR) = 2.1, P = 7 × 10- 8). TT-homozygotes had a 6.5-fold increased risk of hyperbilirubinemia (grades 1-4; 95% confidence interval (CI) = 2.9-14.6, P = 7 × 10- 6) and a 16.4-fold higher risk of grade 3-4 hyperbilirubinemia (95% CI 6.1-43.8, P = 2 × 10- 8). Replication analyses confirmed these associations with joint analysis yielding genome-wide significance (allelic OR = 2.1, P = 6 × 10- 11; 95% CI 1.7-2.7). Moreover, rs6744284 genotypes were strongly linked to the Gilbert's syndrome-associated UGT1A1*28/*37 allele (r2 = 0.70), providing functional support for study findings. Of clinical importance, the rs6744284 TT genotype counterbalanced the adverse prognostic impact of high hyperbilirubinemia on therapy outcome. CONCLUSIONS: Chemotherapy-related hyperbilirubinemia is a prognostic factor for treatment outcome in pediatric ALL and genetic variation in UGT1A aids in predicting the clinical impact of hyperbilirubinemia. TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov ; #NCT00430118.


Assuntos
Estudo de Associação Genômica Ampla , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Bilirrubina/uso terapêutico , Hiperbilirrubinemia/induzido quimicamente , Hiperbilirrubinemia/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Resultado do Tratamento , Criança
9.
Hum Mol Genet ; 19(9): 1840-5, 2010 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-20123861

RESUMO

A recent genome-wide association study of chronic lymphocytic leukaemia (CLL) has identified a susceptibility locus on 6p25.3 associated with a modest but highly significant increase in CLL risk. Using a set of single nucleotide polymorphism (SNP) markers, we generated a fine-scale map and narrowed the association signal to a 18 kb DNA segment within the 3'-untranslated region (UTR) of the IRF4 (interferon regulatory factor 4) gene. Resequencing this segment in European subjects identified 55 common polymorphisms, including 13 highly correlated candidate causal variants. In a large case-control study, it was shown that all but four variants could be excluded with 95% confidence. These four SNPs map to a 3 kb region of the 3'-UTR of IRF4, consistent with the causal basis of the association being mediated through differential IRF4 expression.


Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 6/genética , Predisposição Genética para Doença/genética , Fatores Reguladores de Interferon/genética , Leucemia Linfocítica Crônica de Células B/genética , Regiões 3' não Traduzidas/genética , Sequência de Bases , Estudos de Casos e Controles , Biologia Computacional , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA , Utah , População Branca/genética
10.
Blood ; 115(9): 1765-7, 2010 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-20042726

RESUMO

Recent genome-wide association data have implicated genetic variation at 7p12.2 (IKZF1), 10q21.2 (ARIDB5), and 14q11.2 (CEBPE) in the etiology of B-cell childhood acute lymphoblastic leukemia (ALL). To verify and further examine the relationship between these variants and ALL risk, we genotyped 1384 cases of precursor B-cell childhood ALL and 1877 controls from Germany and the United Kingdom. The combined data provided statistically significant support for an association between genotype at each of these loci and ALL risk; odds ratios (OR), 1.69 (P = 7.51 x10(-22)), 1.80 (P = 5.90 x 10(-28)), and 1.27 (P = 4.90 x 10(-6)), respectively. Furthermore, the risk of ALL increases with an increasing numbers of variant alleles for the 3 loci (OR(per-allele) = 1.53, 95% confidence interval, 1.44-1.62; P(trend) = 3.49 x 10(-42)), consistent with a polygenic model of disease susceptibility. These data provide unambiguous evidence for the role of these variants in defining ALL risk underscoring approximately 64% of cases.


Assuntos
Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 7/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Alelos , Proteínas Estimuladoras de Ligação a CCAAT/genética , Estudos de Casos e Controles , Criança , Proteínas de Ligação a DNA/genética , Feminino , Predisposição Genética para Doença , Genótipo , Alemanha , Humanos , Fator de Transcrição Ikaros/genética , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Reino Unido
11.
Haematologica ; 96(7): 1049-54, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21459794

RESUMO

Acute lymphoblastic leukemia is the major pediatric cancer in developed countries. To date most association studies of acute lymphoblastic leukemia have been based on the candidate gene approach and have evaluated a restricted number of polymorphisms. Such studies have served to highlight difficulties in conducting statistically and methodologically rigorous investigations into acute lymphoblastic leukemia risk. Recent genome-wide association studies of childhood acute lymphoblastic leukemia have provided robust evidence that common variation at four genetic loci confers a modest increase in risk. The accumulated experience to date and relative lack of success of initial efforts to identify novel acute lymphoblastic leukemia predisposition loci emphasize the need for alternative study designs and methods. The International Childhood Acute Lymphoblastic Leukaemia Genetics Consortium includes 12 research groups in Europe, Asia, the Middle East and the Americas engaged in studying the genetics of acute lymphoblastic leukemia. The initial goal of this consortium is to identify and characterize low-penetrance susceptibility variants for acute lymphoblastic leukemia through association-based analyses. Efforts to develop genome-wide association studies of acute lymphoblastic leukemia, in terms of both sample size and single nucleotide polymorphism coverage, and to increase the number of single nucleotide polymorphisms taken forward to large-scale replication should lead to the identification of additional novel risk variants for acute lymphoblastic leukemia. Ethnic differences in the risk of acute lymphoblastic leukemia are well recognized and thus in assessing the interplay between inherited and non-genetic risk factors, analyses using different population cohorts with different incidence rates are likely to be highly informative. Given that the frequency of many acute lymphoblastic leukemia subgroups is small, identifying differential effects will realistically only be possible through multi-center pooled analyses. Here, we review the rationale for identifying genetic risk variants for acute lymphoblastic leukemia and our proposed strategy for establishing the International Childhood Acute Lymphoblastic Leukaemia Genetics Consortium.


Assuntos
Predisposição Genética para Doença , Cooperação Internacional , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Alelos , Criança , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Humanos , Polimorfismo Genético , Pesquisa/normas , Pesquisa/tendências
12.
Hum Mol Genet ; 17(23): 3720-7, 2008 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-18753146

RESUMO

The common single-nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case-control series comprising a total of 10 638 cases and 10 457 healthy individuals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR = 1.17; 95% confidence interval [CI]: 1.12-1.22; P = 1.08 x 10(-12)) with the risk allele more frequent in rectal than colonic disease (P = 0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants, the risk of CRC increases with an increasing numbers of variant alleles for the six loci (OR(per allele) = 1.19; 95% CI: 1.15-1.23; P(trend) = 7.4 x 10(-24)). Using the data from our genome-wide association study of CRC, LD mapping and imputation, we were able to refine the location of the causal locus to a 60 kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression.


Assuntos
Cromossomos Humanos Par 11/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Variação Genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Fatores de Risco
13.
Br J Haematol ; 148(3): 413-5, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19804451

RESUMO

The reciprocal familial risk between chronic lymphocytic leukaemia (CLL) and Hodgkin lymphoma (HL) suggests genetic variants with pleiotropic effects may influence the risk of both CLL and HL. We have recently shown that the IRF4 variant rs872071 influences CLL risk. To examine if rs872071 genotype is associated with HL risk we genotyped two case-control series (totalling, 529 and 2192, respectively). This analysis provides evidence that IRF4 rs872071 influences HL risk; Odds Ratio = 1.21 (95% confidence interval: 1.05-1.39, P = 0.009) and highlights the importance of inherited variation in B-cell developmental genes in the development of HL.


Assuntos
Doença de Hodgkin/genética , Fatores Reguladores de Interferon/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Estudos de Casos e Controles , DNA de Neoplasias/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco/métodos , Adulto Jovem
14.
Haematologica ; 95(8): 1405-14, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20511665

RESUMO

To evaluate the contribution of candidate gene association studies to the understanding of genetic susceptibility to childhood acute lymphoblastic leukemia we conducted a systematic review and meta-analysis of published studies (January 1996-July 2009). Studies had to meet the following criteria: be case-control design, be studied by two or more studies, not be focused on HLA antigen genetic markers and be published in English. We identified 47 studies of polymorphic variation in 16 genes and acute lymphoblastic leukemia risk. To clarify the impact of individual polymorphisms on risk, pooled analyses were performed. Of the 25 polymorphic variants studied, significant associations (P<0.05) were seen in pooled analyses for eight variants: GSTM1 (OR =1.16; 95%CI: 1.04-1.30), MTRR A66G (OR=0.73, 95%CI:0.59-0.91), SHMT1 C1420T (OR=0.79, 95%CI: 0.65-0.98), RFC1 G80A (OR=1.37, 95%CI: 1.11-1.69), CYP1A1*2A (OR=1.36, 95%CI:1.11-1.66), CYP2E1*5B (OR=1.99, 95%CI:1.32-3.00) NQO1 C609T (OR=1.24, 95%CI:1.02-1.50) and XRCC1 G28152A (OR=1.78, 95%CI:1.32-2.42). These findings should, however, be interpreted with caution as the estimated false-positive report probabilities (FPRP) for each association were not noteworthy (i.e. FPRP>0.2). While candidate gene analyses are complementary to genome-wide association studies, future analyses should be based on sample sizes commensurate with the detection of small effects and attention needs to be paid to study design.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Criança , Humanos , Razão de Chances , PubMed , Fatores de Risco
15.
Cancer Epidemiol Biomarkers Prev ; 29(8): 1606-1614, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32467347

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) of childhood cancers remain limited, highlighting the need for novel analytic strategies. We describe a hybrid GWAS and phenome-wide association study (PheWAS) approach to uncover genotype-phenotype relationships and candidate risk loci, applying it to acute lymphoblastic leukemia (ALL). METHODS: PheWAS was performed for 12 ALL SNPs identified by prior GWAS and two control SNP-sets using UK Biobank data. PheWAS-traits significantly associated with ALL SNPs compared with control SNPs were assessed for association with ALL risk (959 cases, 2,624 controls) using polygenic score and Mendelian randomization analyses. Trait-associated SNPs were tested for association with ALL risk in single-SNP analyses, with replication in an independent case-control dataset (1,618 cases, 9,409 controls). RESULTS: Platelet count was the trait most enriched for association with known ALL risk loci. A polygenic score for platelet count (223 SNPs) was not associated with ALL risk (P = 0.82) and Mendelian randomization did not suggest a causal relationship. However, twelve platelet count-associated SNPs were nominally associated with ALL risk in COG data and three were replicated in UK data (rs10058074, rs210142, rs2836441). CONCLUSIONS: In our hybrid GWAS-PheWAS approach, we identify pleiotropic genetic variation contributing to ALL risk and platelet count. Three SNPs known to influence platelet count were reproducibly associated with ALL risk, implicating genomic regions containing IRF1, proapoptotic protein BAK1, and ERG in platelet production and leukemogenesis. IMPACT: Incorporating PheWAS data into association studies can leverage genetic pleiotropy to identify cancer risk loci, highlighting the utility of our novel approach.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Genômica/métodos , Fenômica/métodos , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Estudos de Casos e Controles , Genótipo , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
16.
Leukemia ; 33(1): 1-14, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29977016

RESUMO

Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy. Genome-wide association studies have shown variation at 14q11.2 influences ALL risk. We sought to decipher causal variant(s) at 14q11.2 and the mechanism of tumorigenesis. We show rs2239630 G>A resides in the promoter of the CCAT enhancer-binding protein epsilon (CEBPE) gene. The rs2239630-A risk allele is associated with increased promotor activity and CEBPE expression. Depletion of CEBPE in ALL cells reduces cell growth, correspondingly CEBPE binds to the promoters of electron transport and energy generation genes. RNA-seq in CEBPE depleted cells demonstrates CEBPE regulates the expression of genes involved in B-cell development (IL7R), apoptosis (BCL2), and methotrexate resistance (RASS4L). CEBPE regulated genes significantly overlapped in CEBPE depleted cells, ALL blasts and IGH-CEBPE translocated ALL. This suggests CEBPE regulates a similar set of genes in each, consistent with a common biological mechanism of leukemogenesis for rs2239630 associated and CEBPE translocated ALL. Finally, we map IGH-CEBPE translocation breakpoints in two cases, implicating RAG recombinase activity in their formation.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/genética , Cromossomos Humanos Par 14/genética , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Regiões Promotoras Genéticas , Biomarcadores Tumorais/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Estudos de Casos e Controles , Proliferação de Células , Epigenômica , Humanos , Análise em Microsséries , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Sequências Reguladoras de Ácido Nucleico , Translocação Genética , Células Tumorais Cultivadas
17.
Nat Commun ; 10(1): 5348, 2019 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-31767839

RESUMO

There is increasing evidence for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children. To identify new risk variants for B-cell ALL (B-ALL) we conducted a meta-analysis with four GWAS (genome-wide association studies), totalling 5321 cases and 16,666 controls of European descent. We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P = 2.11 × 10-8), for high-hyperdiploid ALL at 5q31.1 (rs886285, P = 1.56 × 10-8) and 6p21.31 (rs210143 in BAK1, P = 2.21 × 10-8), and ETV6-RUNX1 ALL at 17q21.32 (rs10853104 in IGF2BP1, P = 1.82 × 10-8). Particularly notable are the pleiotropic effects of the BAK1 variant on multiple haematological malignancies and specific effects of IGF2BP1 on ETV6-RUNX1 ALL evidenced by both germline and somatic genomic analyses. Integration of GWAS signals with transcriptomic/epigenomic profiling and 3D chromatin interaction data for these leukaemia risk loci suggests deregulation of B-cell development and the cell cycle as central mechanisms governing genetic susceptibility to ALL.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Predisposição Genética para Doença/genética , Proteínas de Fusão Oncogênica/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas de Ligação a RNA/genética , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Criança , Epigenômica , Estudo de Associação Genômica Ampla , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Fatores de Risco , Transcriptoma
18.
Nat Commun ; 10(1): 419, 2019 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-30664635

RESUMO

The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.

19.
Eur J Hum Genet ; 16(12): 1477-86, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18628789

RESUMO

Previously we have localized to chromosome 3q21-q24, a predisposition locus for colorectal cancer (CRC), through a genome-wide linkage screen (GWLS) of 69 families without familial adenomatous polyposis or hereditary non-polyposis CRC. To further investigate Mendelian susceptibility to CRC, we extended our screen to include a further GWLS of an additional 34 CRC families. We also searched for a disease gene at 3q21-q24 by linkage disequilibrium mapping in 620 familial CRC cases and 960 controls by genotyping 1676 tagging SNPs and sequencing 30 candidate genes from the region. Linkage analysis was conducted using the Affymetrix 10K SNP array. Data from both GWLSs were pooled and multipoint linkage statistics computed. The maximum NPL score (3.01; P=0.0013) across all families was at 3q22, maximal evidence for linkage coming from families segregating rectal CRC. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a dominant model (HLOD=2.79; P=0.00034), with an estimated 43% of families linked. In the case-control analysis, the strongest association was obtained at rs698675 (P=0.0029), but this was not significant after adjusting for multiple testing. Analysis of candidate gene mapping to the region of maximal linkage on 3q22 failed to identify a causal mutation. There was no evidence for linkage to the previously reported 9q CRC locus (NPL=0.95, P=0.23; HLOD(dominant)=0.40, HLOD(recessive)=0.20). Our findings are consistent with the hypothesis that variation at 3q22 contributes to the risk of CRC, but this is unlikely to be mediated through a restricted set of alleles.


Assuntos
Adenoma/genética , Neoplasias Colorretais/genética , Família , Ligação Genética , Estudos de Casos e Controles , Mapeamento Cromossômico , Cromossomos Humanos Par 3 , Análise Mutacional de DNA , Saúde da Família , Dosagem de Genes , Estudo de Associação Genômica Ampla , Humanos , Escore Lod , Polimorfismo de Nucleotídeo Único
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