RESUMO
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.
Assuntos
Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 4/metabolismo , Neoplasias Colorretais/genética , Mutação em Linhagem Germinativa/genética , Adulto , Idoso , Sequência de Aminoácidos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Estrutura Terciária de Proteína , Alinhamento de Sequência , Fator de Crescimento Transformador beta/genéticaRESUMO
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 RiscoRESUMO
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/genéticaRESUMO
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.
Assuntos
Variação Genética , Mutação em Linhagem Germinativa , Leucemia Linfocítica Crônica de Células B/epidemiologia , Receptores CXCR4/genética , Códon sem Sentido , Análise Mutacional de DNA , Frequência do Gene , Genótipo , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Mutação de Sentido Incorreto , Receptores CXCR4/fisiologia , RiscoRESUMO
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.
Assuntos
Cromossomos Humanos Par 18/genética , Neoplasias Colorretais/genética , Polimorfismo de Nucleotídeo Único , Proteína Smad7/genética , Idoso , Alelos , Animais , Linhagem Celular Tumoral , Mapeamento Cromossômico , Neoplasias Colorretais/patologia , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Expressão Gênica , Frequência do Gene , Predisposição Genética para Doença/genética , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Ligação Proteica , Fatores de Risco , Análise de Sequência de DNA , Proteína Smad7/metabolismo , Xenopus laevis/embriologia , Xenopus laevis/genéticaRESUMO
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)).
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 6/genética , Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
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 RiscoRESUMO
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.
Assuntos
Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 8/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Genoma Humano , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alelos , Fator de Iniciação 3 em Eucariotos/genética , Feminino , Ligação Genética , Humanos , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
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.
Assuntos
Mutação em Linhagem Germinativa , Leucemia Linfocítica Crônica de Células B/genética , Proteínas Nucleares/genética , Rad51 Recombinase/genética , Proteína Rad52 de Recombinação e Reparo de DNA/genética , DNA Helicases , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Humanos , Leucemia Linfocítica Crônica de Células B/etiologia , Proteínas de Ligação a RNARESUMO
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)).
Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Adenoma/genética , Linhagem Celular Tumoral , Células Cultivadas , Cromossomos Humanos Par 15 , Humanos , Judeus/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
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)).
Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Genoma Humano , Proteína Smad7/genética , Alelos , Estudos de Casos e Controles , Ligação Genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
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.
Assuntos
Adenocarcinoma/genética , Neoplasias Colorretais/genética , Sistema Enzimático do Citocromo P-450/genética , Predisposição Genética para Doença/epidemiologia , Polimorfismo de Nucleotídeo Único , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Estudos de Casos e Controles , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Intervalos de Confiança , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Razão de Chances , Prognóstico , Valores de Referência , Medição de Risco , Sensibilidade e Especificidade , Análise de SobrevidaRESUMO
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.
