RESUMO
To assess whether DNA repair gene variants influence the clinical behaviour of lung cancer we examined the impact of a comprehensive panel of 109 non-synonymous single-nucleotide polymorphisms (nsSNPs) in 50 DNA repair genes on overall survival (OS) in 700 lung cancer patients. Fifteen nsSNPs were associated with OS, significantly greater than that expected (P = 0.04). SNPs associated with prognosis mapped primarily to two repair pathways--nucleotide excision repair (NER): ERCC5 D1104H (P = 0.004); ERCC6 G399D (P = 0.023), ERCC6 Q1413R (P = 0.025), POLE (P = 0.014) and base excision repair: APEX1 D148E (P = 0.028); EXO1 E670G (P = 0.007); POLB P242R (P = 0.018). An increasing number of variant alleles in EXO1 was associated with a poorer prognosis [hazard ratio (HR) = 1.24; P = 0.0009]. A role for variation in NER and BRCA2/FA pathway genes as determinants of OS was provided by an analysis restricted to the 456 patients treated with platinum-based agents. Our data indicate that the pathway-based approach has the potential to generate prognostic markers of clinical outcome.
Assuntos
Reparo do DNA/genética , Variação Genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Adenosina Trifosfatases/genética , DNA Helicases/genética , DNA Polimerase II/genética , Enzimas Reparadoras do DNA/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Proteínas de Ligação a DNA/genética , DNA Polimerase Dirigida por DNA/genética , Endonucleases/genética , Exodesoxirribonucleases/genética , Genótipo , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Proteínas Nucleares/genética , Proteínas de Ligação a Poli-ADP-Ribose , Prognóstico , RecQ Helicases , Fatores de Transcrição/genética , DNA Polimerase tetaRESUMO
The prognostic significance of the Arg72Pro polymorphism of the p53 tumour suppressor gene in cancer is controversial. To determine whether Arg72Pro is a marker for lung cancer prognosis we genotyped 619 female lung cancer patients with incident disease and examined the relationship between genotype and overall survival (OS). Nonparametric tests provided no evidence for a relationship between SNP genotype and OS (P-values 0.131, 0.161, and 0.156 for log rank, Wilcoxon and Fleming-Harrington test statistics, respectively). Under the Cox proportional hazards model the HRs associated with Arg/Pro, Pro/Pro and Pro-carrier status were: 0.98 (95%CI: 0.79-1.22), 0.76 (95%CI: 0.51-1.15) and 0.93 (95%CI: 0.76-1.15), respectively. Despite employing a comprehensive set of statistical tests including those sensitive to the detection of differences in early survival our data provide little evidence to support the tenet that the p53 Arg72Pro polymorphism is a clinically useful prognostic marker for lung cancer.
Assuntos
Substituição de Aminoácidos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Prolina/metabolismo , Proteína Supressora de Tumor p53/genética , Estudos de Coortes , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Pessoa de Meia-Idade , Estadiamento de Neoplasias/mortalidade , Polimorfismo de Nucleotídeo Único , Prognóstico , 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.
Assuntos
Alelos , Neoplasias Colorretais/genética , Penetrância , Polimorfismo de Nucleotídeo Único/genética , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reino UnidoRESUMO
We conducted a large-scale genome-wide association study in UK Caucasians to identify susceptibility alleles for lung cancer, analyzing 1529 cases and 2707 controls. To increase the likelihood of identifying disease-causing alleles, we genotyped 1476 nonsynonymous single nucleotide polymorphisms (nsSNPs) in 871 candidate cancer genes, biasing SNP selection toward those predicted to be deleterious. Statistically significant associations were identified for 64 nsSNPs, generating a genome-wide significance level of P=0.002. Eleven of the 64 SNPs mapped to genes encoding pivotal components of the growth hormone/insulin-like growth factor (GH-IGF) pathway, including CAMKK1 E375G (OR=1.37, P=5.4x10(-5)), AKAP9 M463I (OR=1.32, P=1.0x10(-4)) and GHR P495T (OR=12.98, P=0.0019). Significant associations were also detected for SNPs within genes in the DNA damage-response pathway, including BRCA2 K3326X (OR=1.72, P=0.0075) and XRCC4 I137T (OR=1.31, P=0.0205). Our study provides evidence that inherited predisposition to lung cancer is in part mediated through low-penetrance alleles and specifically identifies variants in GH-IGF and DNA damage-response pathways with risk of lung cancer.
Assuntos
Hormônio do Crescimento Humano/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Somatomedinas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Apoptose/genética , Estudos de Casos e Controles , Reparo do DNA/genética , Feminino , Predisposição Genética para Doença , Hormônio do Crescimento Humano/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Penetrância , Transdução de Sinais , Somatomedinas/metabolismo , Reino UnidoRESUMO
We conducted a large-scale association study to identify low-penetrance susceptibility alleles for chronic lymphocytic leukemia (CLL), analyzing 992 patients and 2707 healthy controls. To increase the likelihood of identifying disease-causing alleles we genotyped 1467 coding nonsynonymous single nucleotide polymorphisms (nsSNPs) in 865 candidate cancer genes, biasing nsSNP selection toward those predicted to be deleterious. Preeminent associations were identified in SNPs mapping to genes pivotal in the DNA damage-response and cell-cycle pathways, including ATM F858L (odds ratio [OR] = 2.28, P < .0001) and P1054R (OR = 1.68, P = .0006), CHEK2 I157T (OR = 14.83, P = .0008), BRCA2 N372H (OR = 1.45, P = .0032), and BUB1B Q349R (OR = 1.42, P = .0038). Our findings implicate variants in the ATM-BRCA2-CHEK2 DNA damage-response axis with risk of CLL.
Assuntos
Proteína BRCA2/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Leucemia Linfocítica Crônica de Células B/genética , Polimorfismo de Nucleotídeo Único/fisiologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , Idoso , Proteínas Mutadas de Ataxia Telangiectasia , Estudos de Casos e Controles , Ciclo Celular/genética , Quinase do Ponto de Checagem 2 , Dano ao DNA/genética , Reparo do DNA/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Leucemia Linfocítica Crônica de Células B/etiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Nonsynonymous single nucleotide polymorphisms (nsSNP) have the potential to affect the structure or function of expressed proteins and are, therefore, likely to represent modifiers of inherited susceptibility. We have classified and catalogued the predicted functionality of nsSNPs in genes relevant to the biology of cancer to facilitate sequence-based association studies. Candidate genes were identified using targeted search terms and pathways to interrogate the Gene Ontology Consortium database, Kyoto Encyclopedia of Genes and Genomes database, Iobion's Interaction Explorer PathwayAssist Program, National Center for Biotechnology Information Entrez Gene database, and CancerGene database. A total of 9,537 validated nsSNPs located within annotated genes were retrieved from National Center for Biotechnology Information dbSNP Build 123. Filtering this list and linking it to 7,080 candidate genes yielded 3,666 validated nsSNPs with minor allele frequencies > or =0.01 in Caucasian populations. The functional effect of nsSNPs in genes with a single mRNA transcript was predicted using three computational tools-Grantham matrix, Polymorphism Phenotyping, and Sorting Intolerant from Tolerant algorithms. The resultant pool of 3,009 fully annotated nsSNPs is accessible from the Predicted Impact of Coding SNPs database at http://www.icr.ac.uk/cancgen/molgen/MolPopGen_PICS_database.htm. Predicted Impact of Coding SNPs is an ongoing project that will continue to curate and release data on the putative functionality of coding SNPs.
Assuntos
Algoritmos , Predisposição Genética para Doença , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Bases de Dados Genéticas , Humanos , Prognóstico , RNA Mensageiro/biossínteseRESUMO
Folate availability is critical for DNA integrity, required for the transfer of methyl groups in the biosynthesis of thymidilate. Reduction of 5,10-methylenetetrahydrofolate, a donor for methylating dUMP to dTMP in DNA synthesis, to 5-methyltetrahydrofolate, the primary methyl donor for methionine synthesis, is catalyzed by 5,10-methylenetetrahydrofolate reductase (MTHFR). The MTHFR polymorphisms C677T and A1298C have been shown in some studies to alter the risk of a range of different malignancies. We evaluated the role of the C677T and A1298C polymorphisms on chronic lymphocytic leukemia (CLL) risk by genotyping 832 patients and 886 healthy controls. The odds ratio of CLL associated with 677CT and 677TT genotypes were 1.02 [95% confidence interval (95% CI), 0.83-1.24] and 0.90 (95% CI, 0.66-1.24), respectively. The odds ratio of CLL associated with 1298AC and 1298CC genotypes were 0.97 (95% CI, 0.79-1.18) and 0.88 (95% CI, 0.62-1.24), respectively. This data indicate that the MTHFR polymorphisms C677T and A1298C do not significantly contribute to an inherited genetic susceptibility to CLL.
