RESUMEN
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.
Asunto(s)
Alelos , Cromosomas Humanos Par 8/genética , Neoplasias Colorrectales/genética , Factor 3 de Iniciación Eucariótica/genética , Predisposición Genética a la Enfermedad , Variación Genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/patología , Ensayo de Cambio de Movilidad Electroforética , Femenino , Regulación Neoplásica de la Expresión Génica , Genes Reporteros/genética , Sitios Genéticos/genética , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Unión Proteica , Factores de RiesgoRESUMEN
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.
Asunto(s)
Mapeo Cromosómico , Cromosomas Humanos Par 6/genética , Predisposición Genética a la Enfermedad/genética , Factores Reguladores del Interferón/genética , Leucemia Linfocítica Crónica de Células B/genética , Regiones no Traducidas 3'/genética , Secuencia de Bases , Estudios de Casos y Controles , Biología Computacional , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Datos de Secuencia Molecular , Polimorfismo de Nucleótido Simple/genética , Análisis de Secuencia de ADN , Utah , Población Blanca/genéticaRESUMEN
Transforming growth factor-ß (TGF-ß) signalling plays a key role in colorectal cancer (CRC). Bone morphogenetic protein-4 (BMP4) is a member of the TGF-ß family of signal transduction molecules. To examine if germline mutation in BMP4 causes CRC we analysed 504 genetically enriched CRC cases (by virtue of early-onset disease, family history of CRC) for mutations in the coding sequence of BMP4. We identified three pathogenic mutations, p.R286X (g.8330C>T), p.W325C (g.8449G>T) and p.C373S (g.8592G>C), amongst the CRC cases which were not observed in 524 healthy controls. p.R286X localizes to the N-terminal of the TGF-ß1 prodomain truncating the protein prior to the active domain. p.W325C and p.C373S mutations are predicted from protein homology modelling with BMP2 to impact deleteriously on BMP4 function. Segregation of p.C373S with adenoma and hyperplastic polyp in first-degree relatives of the case suggests germline mutations may confer a juvenile polyposis-type phenotype. These findings suggest mutation of BMP4is a cause of CRC and the value of protein-based modelling in the elucidation of rare disease-causing variants.
Asunto(s)
Proteína Morfogenética Ósea 4/genética , Proteína Morfogenética Ósea 4/metabolismo , Neoplasias Colorrectales/genética , Mutación de Línea Germinal/genética , Adulto , Anciano , Secuencia de Aminoácidos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación , Estructura Terciaria de Proteína , Alineación de Secuencia , Factor de Crecimiento Transformador beta/genéticaRESUMEN
A genome-wide linkage scan has provided evidence for a chronic lymphocytic leukemia (CLL) susceptibility locus at 2q21 to which the chemokine receptor CXCR4 gene maps. Recent data provide some evidence for common variation in CXCR4 according to the polymorphic variant rs2228014 defining CLL risk. To examine the role of genetic variation in CXCR4 on CLL risk, we screened 188 familial CLL cases and 213 controls for germline mutations in the coding regions of CXCR4 and genotyped rs2228014 in 1058 CLL cases and 1807 controls. No association between rs2228014 and risk of CLL was seen (P = .83). One truncating (W195X) and 2 missense mutations with possible functional consequences (V139I and G335S) were identified among 186 familial cases and 0 in 213 controls sequenced. Our analysis provides no evidence that common variation in CXCR4 defined by rs228014 influences the risk of CLL, but that functional coding mutations in CXCR4 may contribute to familial CLL.
Asunto(s)
Variación Genética , Mutación de Línea Germinal , Leucemia Linfocítica Crónica de Células B/epidemiología , Receptores CXCR4/genética , Codón sin Sentido , Análisis Mutacional de ADN , Frecuencia de los Genes , Genotipo , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Mutación Missense , Receptores CXCR4/fisiología , RiesgoRESUMEN
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.
Asunto(s)
Cromosomas Humanos Par 11/genética , Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad , Variación Genética , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
BACKGROUND: Cytochrome P450 (CYP) enzymes have the potential to affect colorectal cancer (CRC) risk by determining the genotoxic impact of exogenous carcinogens and levels of sex hormones. METHODS: To investigate if common variants of CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1 and CYP19A1 influence CRC risk we genotyped 2,575 CRC cases and 2,707 controls for 20 single nucleotide polymorphisms (SNPs) that have not previously been shown to have functional consequence within these genes. RESULTS: There was a suggestion of increased risk, albeit insignificant after correction for multiple testing, of CRC for individuals homozygous for CYP1B1 rs162558 and heterozygous for CYP1A2 rs2069522 (odds ratio [OR] = 1.36, 95% confidence interval [CI]: 1.03-1.80 and OR = 1.34, 95% CI: 1.00-1.79 respectively). CONCLUSION: This study provides some support for polymorphic variation in CYP1A2 and CYP1B1 playing a role in CRC susceptibility.
Asunto(s)
Adenocarcinoma/genética , Neoplasias Colorrectales/genética , Sistema Enzimático del Citocromo P-450/genética , Predisposición Genética a la Enfermedad/epidemiología , Polimorfismo de Nucleótido Simple , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Estudios de Casos y Controles , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Intervalos de Confianza , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Oportunidad Relativa , Pronóstico , Valores de Referencia , Medición de Riesgo , Sensibilidad y Especificidad , Análisis de SupervivenciaRESUMEN
Recent genome-wide scans for colorectal cancer (CRC) have revealed the SMAD7 (mothers against decapentaplegic homolog 7) gene as a locus associated with a modest, but highly significant increase in CRC risk. To identify the causal basis of the association between 18q21 variation and CRC, we resequenced the 17-kb region of linkage disequilibrium and evaluated all variants in 2532 CRC cases and 2607 controls. A novel C to G single nucleotide polymorphism (SNP) at 44,703,563 bp was maximally associated with CRC risk (P = 5.98 x 10(-7); > or =1.5-fold more likely to be causal than other variants). Using transgenic assays in Xenopus laevis as a functional model, we demonstrate that the G risk allele leads to reduced reporter gene expression in the colorectum (P = 5.4 x 10(-3)). Electrophoretic mobility shift assays provided evidence for the role of Novel 1 in transcription factor binding. We propose that the novel SNP we have identified is the functional change leading to CRC predisposition through differential SMAD7 expression and, hence, aberrant TGF-beta signaling.
Asunto(s)
Cromosomas Humanos Par 18/genética , Neoplasias Colorrectales/genética , Polimorfismo de Nucleótido Simple , Proteína smad7/genética , Anciano , Alelos , Animales , Línea Celular Tumoral , Mapeo Cromosómico , Neoplasias Colorrectales/patología , Ensayo de Cambio de Movilidad Electroforética , Femenino , Expresión Génica , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/genética , Variación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Proteínas Nucleares/metabolismo , Unión Proteica , Factores de Riesgo , Análisis de Secuencia de ADN , Proteína smad7/metabolismo , Xenopus laevis/embriología , Xenopus laevis/genéticaRESUMEN
While familial predisposition to B-cell chronic lymphocytic leukemia (CLL) is well recognized no gene which when mutated in the germline has been unambiguously shown to confer susceptibility to the disease. An approach based on mutation screening methods targeted to coding regions of candidate genes offers an attractive strategy for the identification of rare disease-causing alleles. The RAD genes participate in the cellular response to DNA double strand breaks, detecting DNA damage, activating cell cycle checkpoints and apoptosis. Defects in members of these genes are linked to increased chromosomal instability and in lymphoma predisposition, thereby representing strong candidate susceptibility genes a priori. To examine this proposition we screened 75 familial CLL probands for germline mutations in this set of genes. No overt pathogenic mutations were identified. These findings indicate that germline mutations in RAD51, RAD51AP1, RAD51L1, RAD51L3, RAD52 and RAD54L are unlikely to be causal of an inherited predisposition to CLL.
Asunto(s)
Mutación de Línea Germinal , Leucemia Linfocítica Crónica de Células B/genética , Proteínas Nucleares/genética , Recombinasa Rad51/genética , Proteína Recombinante y Reparadora de ADN Rad52/genética , ADN Helicasas , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad , Humanos , Leucemia Linfocítica Crónica de Células B/etiología , Proteínas de Unión al ARNRESUMEN
We conducted a genome-wide association (GWA) study of lung cancer comparing 511,919 SNP genotypes in 1,952 cases and 1,438 controls. The most significant association was attained at 15q25.1 (rs8042374; P = 7.75 x 10(-12)), confirming recent observations. Pooling data with two other GWA studies (5,095 cases, 5,200 controls) and with replication in an additional 2,484 cases and 3,036 controls, we identified two newly associated risk loci mapping to 6p21.33 (rs3117582, BAT3-MSH5; P(combined) = 4.97 x 10(-10)) and 5p15.33 (rs401681, CLPTM1L; P(combined) = 7.90 x 10(-9)).
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Cromosomas Humanos Par 5/genética , Cromosomas Humanos Par 6/genética , Predisposición Genética a la Enfermedad , Neoplasias Pulmonares/genética , Estudios de Casos y Controles , Estudio de Asociación del Genoma Completo , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
We mapped a high-penetrance gene (CRAC1; also known as HMPS) associated with colorectal cancer (CRC) in the Ashkenazi population to a 0.6-Mb region on chromosome 15 containing SCG5 (also known as SGNE1), GREM1 and FMN1. We hypothesized that the CRAC1 locus harbored low-penetrance variants that increased CRC risk in the general population. In a large series of colorectal cancer cases and controls, SNPs near GREM1 and SCG5 were strongly associated with increased CRC risk (for rs4779584, P = 4.44 x 10(-14)).
Asunto(s)
Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad , Adenoma/genética , Línea Celular Tumoral , Células Cultivadas , Cromosomas Humanos Par 15 , Humanos , Judíos/genética , Polimorfismo de Nucleótido SimpleRESUMEN
To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 x 10(-13) overall; P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall; P = 9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.
Asunto(s)
Cromosomas Humanos Par 10/genética , Cromosomas Humanos Par 8/genética , Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad , Genoma Humano , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Alelos , Factor 3 de Iniciación Eucariótica/genética , Femenino , Ligamiento Genético , Humanos , Masculino , Persona de Mediana Edad , LinajeRESUMEN
To identify risk variants for colorectal cancer (CRC), we conducted a genome-wide association study, genotyping 550,163 tag SNPs in 940 individuals with familial colorectal tumor (627 CRC, 313 advanced adenomas) and 965 controls. We evaluated selected SNPs in three replication sample sets (7,473 cases, 5,984 controls) and identified three SNPs in SMAD7 (involved in TGF-beta and Wnt signaling) associated with CRC. Across the four sample sets, the association between rs4939827 and CRC was highly statistically significant (P(trend) = 1.0 x 10(-12)).
Asunto(s)
Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad , Genoma Humano , Proteína smad7/genética , Alelos , Estudios de Casos y Controles , Ligamiento Genético , Genotipo , Humanos , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
To identify low penetrance susceptibility alleles for colorectal cancer (CRC), we genotyped 1467 non-synonymous SNPs mapping to 871 candidate cancer genes in 2575 cases and 2707 controls. nsSNP selection was biased towards those predicted to be functionally deleterious. One SNP AKAP9 M463I remained significantly associated with CRC risk after stringent adjustment for multiple testing. Further SNPs associated with CRC risk included several previously reported to be associated with cancer risk including ATM F858L [OR=1.48; 95% confidence interval (CI): 1.06-2.07] and P1054R (OR=1.42; 95% CI: 1.14-1.77) and MTHFR A222V (OR=0.82; 95% CI: 0.69-0.97). To validate associations, we performed a kin-cohort analysis on the 14 704 first-degree relatives of cases for each SNP associated at the 5% level in the case-control analysis employing the marginal maximum likelihood method to infer genotypes of relatives. Our observations support the hypothesis that inherited predisposition to CRC is in part mediated through polymorphic variation and identify a number of SNPs defining inter-individual susceptibility. We have made data from this analysis publicly available at http://www.icr.ac.uk/research/research_sections/cancer_genetics/cancer_genetics_teams/molecular_and_population_genetics/software_and_databases/index.shtml in order to facilitate the identification of low penetrance CRC susceptibility alleles through pooled analyses.