RESUMEN
The tobacco-specific nitrosamine NNK is a potent carcinogen found in tobacco smoke and implicated in the development of lung cancer. The major route of NNK metabolism is carbonyl reduction by AKR1C1, AKR1C2, CBR1, and 11ß-HSD1 to form NNAL. This study investigated the potential role of variants in this pathway on lung cancer risk by examining 53 tag-SNPs representing the common variations in AKR1C1, AKR1C2, CBR1, and HSD11B1 in 456 lung cancer cases and 807 controls. One SNP in CBR1 (rs2835267) was significantly associated with overall risk of lung cancer, but did not pass multiple testing adjustment (OR: 0.76 95% CI: 0.58-0.99, P = 0.048, FDR P = 0.20). After stratification and multiple testing correction, three SNPs showed significance. One SNP (rs2835267) in CBR1 showed a significant decreased risk for smokers with a high pack-years (OR: 0.3595% CI: 0.17-0.69, P = 0.018) and in SCC (OR: 0.4895% CI: 0.29-0.76, P = 0.018). Another SNP located in CBR1 (rs3787728) also showed a significant decreased risk in SCC (OR: 0.4695% CI: 0.26-0.80, P = 0.024) and small cell carcinoma (only in current smokers) (OR: 0.06895% CI: 0.01-0.42, P = 0.028). The HSD11B1 SNP (rs4844880) showed a significant increased risk for adenocarcinoma within former smokers (OR: 3.9495% CI: 1.68-9.22, P = 0.011). Haplotype analysis found significance with six haplotypes and lung cancer risk. These findings indicate that select variants in genes in the carbonyl reduction pathway of NNK may alter the risk of lung cancer.
Asunto(s)
Predisposición Genética a la Enfermedad , Neoplasias Pulmonares/genética , Nitrosaminas/farmacología , Polimorfismo de Nucleótido Simple , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
UDP-glucuronosyltransferases (UGTs) play an important role in the phase II metabolism of exogenous and endogenous compounds. As colorectal cancer (CRC) etiology is thought to involve the biotransformation of dietary factors, UGT polymorphisms may affect CRC risk by altering levels of exposure. Genotyping of over 1800 Caucasian subjects was completed to identify the role of genetic variation in nine UGT1A and five UGT2B genes on CRC risk. Unconditional logistic regression and haplotype analyses were conducted to identify associations with CRC risk and potential gene-environment interactions. UGT1A haplotype analysis found that the T-G haplotype in UGT1A10 exon 1 (block 2: rs17864678, rs10929251) decreased cancer risk for the colon [proximal (OR = 0.28, 95% CI = 0.110.69) and for the distal colon (OR = 0.32, 95% CI = 0.120.91)], and that the C-T-G haplotype in the 3' region flanking the UGT1A shared exons (block 11: rs7578153, rs10203853, rs6728940) increased CRC risk in males (OR = 2.56, 95% CI = 1.105.95). A haplotype in UGT2B15 containing a functional variant (rs4148269, K523T) and an intronic SNP (rs6837575) was found to affect rectal cancer risk overall (OR = 2.57, 95% CI = 1.215.04) and in females (OR = 3.08, 95% CI = 1.088.74). An interaction was found between high NSAID use and the A-G-T haplotype (block 10: rs6717546, rs1500482, rs7586006) in the UGT1A shared exons that decreased CRC risk. This suggests that UGT genetic variation alters CRC risk differently by anatomical sub-site and gender and that polymorphisms in the UGT1A shared exons may have a regulatory effect on gene expression that allows for the protective effect of NSAIDs on CRC risk.
Asunto(s)
Neoplasias Colorrectales/genética , Interacción Gen-Ambiente , Glucuronosiltransferasa/genética , Polimorfismo de Nucleótido Simple , Anciano , Antiinflamatorios no Esteroideos/uso terapéutico , Estudios de Casos y Controles , Cromosomas Humanos Par 2 , Cromosomas Humanos Par 4 , Neoplasias Colorrectales/metabolismo , Femenino , Estudios de Asociación Genética , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Riesgo , Factores de RiesgoRESUMEN
Previous research has shown that greater intakes of dietary folate are associated with reduced risk for colorectal cancer (CRC) and that single nucleotide polymorphisms (SNPs) in genes involved in folate-mediated one-carbon metabolism (FOCM) also may be involved in altering CRC risk. The objective of this study was to evaluate the role of folate intake (and intakes of related dietary components such as methionine), 35 SNPs in three FOCM pathway genes (MTHFD1, MTHFR, and TYMS), and their interactions on CRC risk in a population-based case-control study in Pennsylvania (686 cases, 740 controls). Diet and supplement use was assessed for the year before diagnosis or interview for cases and controls, respectively, with a modified Diet History Questionnaire from the National Cancer Institute. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using unconditional logistic regression. Using a dominant model for the variant allele, several SNPs were significantly associated with CRC including MTHFD1 rs8003379 (OR = 1.65; 95% CI = 1.00-2.73) and rs17824591 (OR = 1.98; 95% CI = 1.14-3.41) and the TYMS rs2853533 SNP (OR = 1.38; 95% CI = 1.05-1.80). Using a nondominant model, the AA genotype for MTHFR rs1476413 exhibited a marginally significant (OR = 1.56; 95% CI = 1.00-2.44) association with CRC. Two TYMS SNPs (rs16948305 and rs495139) exhibited significant (P = 0.024 and P = 0.040, respectively) gene-diet interactions with folate intake. One MTHFD1 (P = 0.019) and one MTHFR (P = 0.042) SNP exhibited gene-diet interactions with methionine intake. These findings suggest that allelic variants in genes involved in FOCM interact with dietary factors including folate and methionine to modify risk for CRC.
Asunto(s)
Neoplasias Colorrectales/epidemiología , Ácido Fólico/administración & dosificación , Metilenotetrahidrofolato Deshidrogenasa (NADP)/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Anciano , Estudios de Casos y Controles , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Dieta , Suplementos Dietéticos , Femenino , Ácido Fólico/metabolismo , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Antígenos de Histocompatibilidad Menor , Pennsylvania/epidemiología , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Genetic polymorphisms in combination with the Western-style diet, physical inactivity, smoking, excessive alcohol consumption, and obesity have been hypothesized to affect colorectal cancer (CRC) risk. Metabolizers of environmental carcinogenic and endogenous compounds affecting CRC risk include the phase II detoxification UDP-glucuronosyltransferase (UGT) enzymes UGT2B17 and UGT2B28, which are 2 of the most commonly deleted genes in the genome. METHODS: To study the effect of UGT2B17 and UGT2B28 copy number variation (CNV) on CRC risk, 665 Caucasian CRC cases and 621 Caucasian controls were genotyped who had completed extensive demographics and lifestyle questionnaires. RESULTS: A significant association between the UGT2B17 deletion genotype (0/0) and decreased CRC risk was found when the entire population was analyzed (P = .044). Stratification by sex yielded a decreased risk (P = .020) in men with the UGT2B17 deletion (0/0), but no association was observed in women (P = .724). A significant association between UGT2B17 (0/0) and decreased risk for rectal (P = .0065) but not colon cancer was found. No significant association was found between UGT2B28 CNV and CRC risk. CONCLUSIONS: The UGT2B17 deletion genotype (0/0) was associated with a decreased CRC risk in a Caucasian population. After sex stratification, the association was observed in men but not in women, which is consistent with previous findings that men have higher UGT2B17 expression and activity than women. Because UGT2B17 metabolizes certain nonsteroidal anti-inflammatory drugs and flavonoids with antioxidative properties, individuals with a gene deletion may have higher levels of these protective dietary components.
Asunto(s)
Neoplasias Colorrectales/genética , Variaciones en el Número de Copia de ADN , Eliminación de Gen , Glucuronosiltransferasa/genética , Fase II de la Desintoxicación Metabólica/genética , Adulto , Anciano , Estudios de Casos y Controles , Neoplasias del Colon/genética , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/epidemiología , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Carne/efectos adversos , Productos de la Carne/efectos adversos , Persona de Mediana Edad , Antígenos de Histocompatibilidad Menor , Pennsylvania/epidemiología , Neoplasias del Recto/genética , Factores de Riesgo , Factores Sexuales , Encuestas y Cuestionarios , Población Blanca/genéticaRESUMEN
BACKGROUND: Previously we performed a linkage scan of 638 African American affected sibling pairs (ASP) with type 2 diabetes (T2D) enriched for end-stage renal disease (ESRD). Ordered subset linkage analysis (OSA) revealed a linkage peak on chromosome 7p in the subset of families with earlier age of T2D diagnosis. METHODS: We fine mapped this region by genotyping 11 additional polymorphic markers in the same ASP and investigated a total of 68 single nucleotide polymorphisms (SNPs) in functional candidate genes (GCK1, IL6, IGFBP1 and IGFBP3) for association with age of T2D diagnosis, age of ESRD diagnosis, duration of T2D to onset of ESRD, body mass index (BMI) in African American cases and T2D-ESRD in an African American case-control cohort. OSA of fine mapping markers supported linkage at 28 cM on 7p (near D7S3051) in early-onset T2D families (max. LOD = 3.61, P = 0.002). SNPs in candidate genes and 70 ancestry-informative markers (AIMs) were evaluated in 577 African American T2D-ESRD cases and 596 African American controls. RESULTS: The most significant association was observed between ESRD age of diagnosis and SNP rs730497, located in intron 1 of the GCK1 gene (recessive T2D age-adjusted P = 0.0006). Nominal associations were observed with GCK1 SNPs and T2D age of diagnosis (BMI-adjusted P = 0.014 to 0.032). Also, one IGFBP1 and four IGFBP3 SNPs showed nominal genotypic association with T2D-ESRD (P = 0.002-0.049). After correcting for multiple tests, only rs730497 remanined significant. CONCLUSION: Variant rs730947 in the GCK1 gene appears to play a role in early ESRD onset in African Americans.
Asunto(s)
Población Negra/genética , Cromosomas Humanos Par 7/genética , Diabetes Mellitus Tipo 2/genética , Nefropatías Diabéticas/etiología , Ligamiento Genético/genética , Fallo Renal Crónico/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Edad de Inicio , Índice de Masa Corporal , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/etnología , Nefropatías Diabéticas/etnología , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Quinasas del Centro Germinal , Humanos , Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/genética , Interleucina-6/genética , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/etnología , Masculino , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Proteínas Serina-Treonina Quinasas/genética , Factores de RiesgoRESUMEN
UDP-glucuronosyltransferases (UGTs) are enzymes involved in the metabolism of steroid hormones, carcinogens, cancer chemotherapy agents, and addictive agents from cigarettes. Because the UGT2B family of genes has been linked to hormonal regulation in human cell lines in vitro, we hypothesized that there may be sex-related differences in the expression and activity of these genes in human tissues. To evaluate whether there are sex differences in UGT2B expression and activity, we examined 103 normal human liver specimens for UGT2B expression by real-time polymerase chain reaction and in vitro glucuronidation activities in human liver microsomes (HLM). Men exhibited an approximately 4-fold higher level of expression of UGT2B17 than women (p = 0.007). Consistent with the increased expression of UGT2B17 in men, HLM from men also had a higher level of glucuronidation activity than HLM from women against three UGT2B17 substrates: 3-fold higher for 17-dihydroexemestane (p = 0.002); 3-fold higher for 3-hydroxycotinine (p < 0.001); and 1.5-fold higher for suberoylanilide hydroxamic acid (p = 0.014). When we stratified by UGT2B17 gene deletion genotype, similar patterns were observed for all three substrates, with HLM from men with the UGT2B17 (+/+) or (+/0) genotypes exhibiting significantly higher levels of glucuronidation activity against all three substrates compared with HLM from women. These data suggest that men have a higher amount of UGT2B17 glucuronidation activity then women. This sex difference in UGT2B17 gene expression and corresponding protein activity could potentially result in different levels of carcinogen detoxification or drug elimination in men versus women.
Asunto(s)
Glucuronosiltransferasa/genética , Caracteres Sexuales , Femenino , Regulación Enzimológica de la Expresión Génica , Glucurónidos/metabolismo , Glucuronosiltransferasa/metabolismo , Humanos , Masculino , Microsomas Hepáticos/enzimología , Antígenos de Histocompatibilidad Menor , ARN Mensajero/análisisRESUMEN
Microsomal epoxide hydrolase (EPHX1) biotransforms epoxide derivatives of pharmaceuticals, including metabolites of certain antiepileptic medications, such as phenytoin and carbamazepine, and many environmental epoxides, such as those derived from butadiene, benzene, and carcinogenic polyaromatic hydrocarbons. We previously identified a far upstream promoter region, designated E1-b, in the EPHX1 gene that directs expression of an alternatively spliced EPHX1 mRNA transcript in human tissues. In this investigation, we characterized the structural features and expression character of the E1-b promoter region. Results of quantitative real-time polymerase chain reaction analyses demonstrated that the E1-b variant transcript is preferentially and broadly expressed in most tissues, such that it accounts for the majority of total EPHX1 transcript in vivo. Comparative genomic sequence comparisons indicated that the human EPHX1 E1-b gene regulatory region is primate-specific. Direct sequencing and genotyping approaches in 450 individuals demonstrated that the E1-b promoter region harbors a series of transposable element cassettes, including a polymorphic double Alu insertion. Results of reporter assays conducted in several human cell lines demonstrated that the inclusion of the Alu(+/+) insertion significantly decreases basal transcriptional activities. Furthermore, using haplotype block analyses, we determined that the E1-b polymorphic promoter region was not in linkage disequilibrium with two previously identified nonsynonomous single nucleotide polymorphisms (SNPs) in the coding region or with functional SNPs previously identified in the proximal promoter region of the gene. These results demonstrate that the upstream E1-b promoter is the major regulator of EPHX1 expression in human tissues and that polymorphism in this region may contribute an interindividual risk determinant to xenobiotic-induced toxicities.
Asunto(s)
Epóxido Hidrolasas/genética , Regulación Enzimológica de la Expresión Génica/fisiología , Polimorfismo Genético/fisiología , Regiones Promotoras Genéticas/fisiología , Animales , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Epóxido Hidrolasas/biosíntesis , Epóxido Hidrolasas/metabolismo , Variación Genética/fisiología , Humanos , Macaca mulatta , Pan troglodytes , Transcripción GenéticaRESUMEN
The estrogen receptor-alpha gene (ESR1) was selected as a positional candidate under a type 2 diabetes linkage peak at 6q24-27. A total of 42 ESR1 single nucleotide polymorphisms (SNPs) were genotyped in 380 African-American type 2 diabetic case subjects with end-stage renal disease (ESRD) and 276 African-American control subjects. A total of 22 ancestry informative markers were also genotyped, and the program Admixmap was used to adjust allelic and haplotypic association tests for individual estimates of admixture. The most significant association with type 2 diabetes-ESRD was with rs1033182 in intron 2 (P = 0.013, admixture-adjusted P(a) = 0.021). Genotyping 17 SNPs across a region of ESR1 intron 1-intron 2 in an expanded population of 851 case and 635 control subjects supported association with rs1033182 (P = 0.004, P(a) = 0.027) and with an independent six-SNP haplotype of high linkage disequilibrium spanning 6.4 kb (P < 0.0001, P(a) < 0.0001). The same 17 ESR1 SNPs were genotyped in 300 European-American type 2 diabetes-ESRD case subjects and 310 European-American control subjects. Two intron 2 SNPs, rs2431260 (P = 0.015) and rs1709183 (P = 0.019), and a four-SNP haplotype containing these SNPs (P = 0.033) were associated with type 2 diabetes and/or ESRD. Results suggest that intron 1 and intron 2 of the ESR1 gene may contain functionally important regions related to type 2 diabetes or ESRD risk.
Asunto(s)
Negro o Afroamericano/genética , Diabetes Mellitus Tipo 2/genética , Nefropatías Diabéticas/complicaciones , Nefropatías Diabéticas/genética , Receptor alfa de Estrógeno/genética , Fallo Renal Crónico/genética , Población Blanca/genética , Anciano , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/complicaciones , Exones/genética , Femenino , Ligamiento Genético , Predisposición Genética a la Enfermedad , Humanos , Intrones/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone is a potent and abundant procarcinogen found in tobacco smoke, and glucuronidation of its major metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), by UDP-glucuronosyltransferases (UGT) including UGT2B17 is an important mechanism for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone detoxification. Both copies of the UGT2B17 gene are deleted in approximately 10% of Whites and the deletion is associated with a reduction in NNAL glucuronidation activity in vitro. In this study, we examined the effects of the UGT2B17 deletion (0/0) on NNAL glucuronidation rates in a sample of 82 healthy cigarette smokers and further examined its effects on lung cancer risk in a separate case-control study. In the healthy smokers study, a lower urinary ratio of NNAL-glucuronide to NNAL was observed in women with the UGT2B17 deletion (0/0) as compared with women with either the wild-type or heterozygous genotypes (P = 0.058). There were no significant differences in this ratio by genotype in men (P = 0.597). In the case-control study of 398 lung cancer patients and 697 community controls, the UGT2B17 deletion (0/0) was associated with a significant increase in risk of lung cancer in women (odds ratio, 2.0; 95% confidence interval, 1.01-4.0). The risk for the subset of women with lung adenocarcinoma was 2.8 (95% confidence interval, 1.2-6.3). The deletion was not associated with other lung histologic types in women and was not associated with the risk for any lung histologic types in men. The association of the UGT2B17 deletion with increased lung adenocarcinoma in women is consistent with its association with decreased NNAL glucuronidation rates in women and with studies showing that NNAL is a selective inducer of lung adenocarcinoma in experimental animals.
Asunto(s)
Adenocarcinoma/enzimología , Adenocarcinoma/genética , Glucuronosiltransferasa/genética , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Nitrosaminas/orina , Piridinas/orina , Adenocarcinoma/epidemiología , Biomarcadores de Tumor/genética , Estudios de Casos y Controles , Estudios Transversales , Femenino , Florida/epidemiología , Eliminación de Gen , Genotipo , Humanos , Modelos Logísticos , Neoplasias Pulmonares/epidemiología , Masculino , New York/epidemiología , Fenotipo , Riesgo , Fumar/epidemiologíaRESUMEN
Chronic inflammation associated with inflammatory bowel disease (IBD) results in increased oxidative stress that damages the colonic microenvironment. Low levels of serum bilirubin, an endogenous antioxidant, have been associated with increased risk for Crohn's disease (CD). Therefore, the aim of this study was to examine whether total serum bilirubin levels are associated with ulcerative colitis (UC). We identified a retrospective case-control population (n = 6,649) from a single tertiary care center, Penn State Hershey Medical Center (PSU) and a validation cohort (n = 1,996) from Virginia Commonwealth University Medical Center (VCU). Cases were age- and sex-matched to controls (PSU: CD n = 254, UC n = 187; VCU: CD n = 233, UC n = 124). Total serum bilirubin levels were obtained from de-identified medical records and segregated into quartiles. Logistic regression analysis was performed on each quartile of total serum bilirubin compared to the last quartile (highest bilirubin levels) to determine the association of total serum bilirubin with UC. Similar to CD patients, UC patients demonstrated reduced levels of total serum bilirubin compared to controls at PSU and VCU. The lowest quartile of total serum bilirubin was independently associated with UC for the PSU (OR: 1.98 [95% CI: 1.09-3.63]) and VCU cohorts (OR: 6.07 [95% CI: 3.01-12.75]). Lower levels of the antioxidant bilirubin may reduce the capability of UC patients to remove reactive oxygen species leading to an increase in intestinal injury. Therapeutics that reduce oxidative stress may be beneficial for these patients.
Asunto(s)
Bilirrubina/sangre , Colitis Ulcerosa/sangre , Adulto , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
BACKGROUND: Epidemiologic evidence indicates that greater intakes of vitamin D may decrease the risk of colorectal cancer. Variants in the vitamin D receptor (VDR) gene have the potential to modify associations between vitamin D intake and colorectal cancer. METHODS: Associations between intakes of vitamin D and colorectal cancer were studied in a large case-control study conducted in central and northeastern Pennsylvania including 1,012 cases with histologically confirmed colorectal cancer and 1,080 population-based controls. Associations between 35 tagSNPs encompassing the VDR gene and risk for colorectal cancer as well as gene-diet associations were also assessed among a subset of the population (770 controls, 710 cases). RESULTS: No significant trends were observed between vitamin D intake and colorectal cancer risk. After adjustment for multiple comparisons, none of the SNPs or haplotypes within the VDR gene were associated with colorectal cancer. There were also no interactions between dietary factors and variants in the entire VDR gene. CONCLUSIONS: Overall, results from this study suggest that vitamin D intake and variants in the VDR gene have little effect on risk for colorectal cancer. IMPACT: Increasing vitamin D intake from the diet may not result in decreasing the incidence of colorectal cancer.
Asunto(s)
Neoplasias Colorrectales/genética , ADN de Neoplasias/genética , Polimorfismo Genético , Vigilancia de la Población , Receptores de Calcitriol/genética , Vitamina D/administración & dosificación , Anciano , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Frecuencia de los Genes , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Pennsylvania/epidemiología , Receptores de Calcitriol/metabolismo , Estudios Retrospectivos , Factores de Riesgo , Vitaminas/administración & dosificaciónRESUMEN
BACKGROUND: The formation of bulky DNA adducts caused by diol epoxide derivatives of polycyclic aromatic hydrocarbons has been associated with tobacco-induced cancers, and inefficient repair of such adducts by the nucleotide excision repair (NER) system has been linked to increased risk of tobacco-induced lung and head and neck (H&N) cancers. The human excision repair cross-complementation group 1 (ERCC1) protein is essential for a functional NER system and genetic variation in ERCC1 may contribute to impaired DNA repair capacity and increased lung and H&N cancer risk. METHODS: In order to comprehensively capture common genetic variation in the ERCC1 gene, Caucasian data from the International HapMap project was used to assess linkage disequilibrium and choose four tagSNPs (rs1319052, rs3212955, rs3212948, and rs735482) in the ERCC1 gene to genotype 452 lung cancer cases, 175 H&N cancer cases, and 790 healthy controls. Haplotypes were estimated using expectation maximization (EM) algorithm, and haplotype association with cancer was investigated using Haplo.stats software adjusting for known covariates. RESULTS: The genotype and haplotype frequencies matched previous estimates from Caucasians. There was no significant difference in the prevalence of rs1319052, rs3212955, rs3212948, and rs735482 when comparing lung or H&N cancer cases with controls (p-values>0.05). Similarly, there was no association between ERCC1 haplotypes and lung or H&N cancer susceptibility in this Caucasian population (p-values>0.05). No associations were found when stratifying lung cancer cases by histology, sex, smoking status, or smoking intensity. CONCLUSIONS: This study suggests that ERCC1 polymorphisms and haplotypes do not play a role in lung and H&N cancer susceptibility in Caucasians.
Asunto(s)
Proteínas de Unión al ADN/genética , Endonucleasas/genética , Neoplasias de Cabeza y Cuello/genética , Neoplasias Pulmonares/genética , Estudios de Casos y Controles , Reparación del ADN , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Neoplasias de Cabeza y Cuello/etnología , Humanos , Neoplasias Pulmonares/etnología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Fumar/efectos adversos , Fumar/genética , Población Blanca/genéticaRESUMEN
Glucuronidation is an important pathway in the metabolism of nicotine, with previous studies suggesting that â¼22% of urinary nicotine metabolites are in the form of glucuronidated compounds. Recent in vitro studies have suggested that the UDP-glucuronosyltransferases (UGT) 2B10 and 2B17 play major roles in nicotine glucuronidation with polymorphisms in both enzymes shown to significantly alter the levels of nicotine-glucuronide, cotinine-glucuronide, and trans-3'-hydroxycotinine (3HC)-glucuronide in human liver microsomes in vitro. In the present study, the relationship between the levels of urinary nicotine metabolites and functional polymorphisms in UGTs 2B10 and 2B17 was analyzed in urine specimens from 104 Caucasian smokers. Based on their percentage of total urinary nicotine metabolites, the levels of nicotine-glucuronide and cotinine-glucuronide were 42% (P < 0.0005) and 48% (P < 0.0001), respectively, lower in the urine from smokers exhibiting the UGT2B10 (*1/*2) genotype and 95% (P < 0.05) and 98% (P < 0.05), respectively, lower in the urine from smokers with the UGT2B10 (*2/*2) genotype compared with the urinary levels in smokers having the wild-type UGT2B10 (*1/*1) genotype. The level of 3HC-glucuronide was 42% (P < 0.001) lower in the urine from smokers exhibiting the homozygous UGT2B17 (*2/*2) deletion genotype compared with the levels in urine from wild-type UGT2B17 subjects. These data suggest that UGTs 2B10 and 2B17 play important roles in the glucuronidation of nicotine, cotinine, and 3HC and suggest that the UGT2B10 codon 67 SNP and the UGT2B17 gene deletion significantly reduce overall glucuronidation rates of nicotine and its major metabolites in smokers.
Asunto(s)
Glucuronosiltransferasa/genética , Nicotina/orina , Adulto , Anciano , Femenino , Genotipo , Glucurónidos/orina , Glucuronosiltransferasa/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Antígenos de Histocompatibilidad Menor , Mucosa Bucal/citología , Mucosa Bucal/enzimología , Polimorfismo Genético , Fumar/genética , Fumar/orinaRESUMEN
The FOXO family of transcription factors elicits cell cycle arrest, apoptosis, and resistance to various physiologic and pathologic stresses relevant to sporadic cancer, such as DNA damage and oxidative stress. Although implicated as tumor suppressors, FOXO genetic inactivation has not been observed in human cancer. In an investigation of the two major types of non-small cell lung cancer, here, we identify the FOXO3 gene as a novel target of deletion in human lung adenocarcinoma (LAC). Biallelic or homozygous deletion (HD) of FOXO3 was detected in 8 of 33 (24.2%) mostly early-stage LAC of smokers. Another 60.6% of these tumors had losses of FOXO3 not reaching the level of HD (hereafter referred to as sub-HD). In contrast, no HD of FOXO3 was observed in 19 lung squamous cell carcinoma. Consistent with the deletion of FOXO3 were corresponding decreases in its mRNA and protein levels in LAC. The potential role of FOXO3 loss in LAC was also investigated. The carcinogen (+)-anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) is strongly implicated as a cause of human lung cancer. Here, we show that FOXO3a is functionally activated and augments the level of caspase-dependent apoptosis in cells exposed to this DNA-damaging carcinogen. These results implicate FOXO3 as a suppressor of LAC carcinogenesis, a role frequently lost through gene deletion.
Asunto(s)
Adenocarcinoma/inducido químicamente , Adenocarcinoma/genética , Carcinógenos , Factores de Transcripción Forkhead/genética , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/genética , 7,8-Dihidro-7,8-dihidroxibenzo(a)pireno 9,10-óxido , Apoptosis/genética , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/genética , Cocarcinogénesis , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/biosíntesis , Eliminación de Gen , Genes Supresores de Tumor , Humanos , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Activación TranscripcionalRESUMEN
BACKGROUND: Genome-wide association studies have identified three chromosomal regions at 15q25, 5p15, and 6p21 as being associated with the risk of lung cancer. To confirm these associations in independent studies and investigate heterogeneity of these associations within specific subgroups, we conducted a coordinated genotyping study within the International Lung Cancer Consortium based on independent studies that were not included in previous genome-wide association studies. METHODS: Genotype data for single-nucleotide polymorphisms at chromosomes 15q25 (rs16969968, rs8034191), 5p15 (rs2736100, rs402710), and 6p21 (rs2256543, rs4324798) from 21 case-control studies for 11 645 lung cancer case patients and 14 954 control subjects, of whom 85% were white and 15% were Asian, were pooled. Associations between the variants and the risk of lung cancer were estimated by logistic regression models. All statistical tests were two-sided. RESULTS: Associations between 15q25 and the risk of lung cancer were replicated in white ever-smokers (rs16969968: odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.21 to 1.32, P(trend) = 2 x 10(-26)), and this association was stronger for those diagnosed at younger ages. There was no association in never-smokers or in Asians between either of the 15q25 variants and the risk of lung cancer. For the chromosome 5p15 region, we confirmed statistically significant associations in whites for both rs2736100 (OR = 1.15, 95% CI = 1.10 to 1.20, P(trend) = 1 x 10(-10)) and rs402710 (OR = 1.14, 95% CI = 1.09 to 1.19, P(trend) = 5 x 10(-8)) and identified similar associations in Asians (rs2736100: OR = 1.23, 95% CI = 1.12 to 1.35, P(trend) = 2 x 10(-5); rs402710: OR = 1.15, 95% CI = 1.04 to 1.27, P(trend) = .007). The associations between the 5p15 variants and lung cancer differed by histology; odds ratios for rs2736100 were highest in adenocarcinoma and for rs402710 were highest in adenocarcinoma and squamous cell carcinomas. This pattern was observed in both ethnic groups. Neither of the two variants on chromosome 6p21 was associated with the risk of lung cancer. CONCLUSIONS: In this international genetic association study of lung cancer, previous associations found in white populations were replicated and new associations were identified in Asian populations. Future genetic studies of lung cancer should include detailed stratification by histology.
Asunto(s)
Pueblo Asiatico/genética , Cromosomas Humanos Par 15 , Cromosomas Humanos Par 5 , Cromosomas Humanos Par 6 , Neoplasias Pulmonares/etnología , Neoplasias Pulmonares/genética , Polimorfismo de Nucleótido Simple , Fumar/efectos adversos , Tabaquismo/etnología , Tabaquismo/genética , Población Blanca/genética , Adenocarcinoma/etnología , Adenocarcinoma/genética , Adulto , Anciano , Anciano de 80 o más Años , Canadá/epidemiología , Carcinoma de Células Grandes/etnología , Carcinoma de Células Grandes/genética , Carcinoma de Células Pequeñas/etnología , Carcinoma de Células Pequeñas/genética , Carcinoma de Células Escamosas/etnología , Carcinoma de Células Escamosas/genética , Estudios de Casos y Controles , Europa (Continente) , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Homocigoto , Humanos , Cooperación Internacional , Japón/epidemiología , Corea (Geográfico)/epidemiología , Desequilibrio de Ligamiento/genética , Neoplasias Pulmonares/etiología , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Control de Calidad , Medición de Riesgo , Factores de Riesgo , Singapur/epidemiología , Fumar/genética , Estados Unidos/epidemiologíaRESUMEN
Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase inhibitor used in the treatment of cutaneous T-cell lymphoma and in clinical trials for treatment of multiple other cancers. A major mode of SAHA metabolism is by glucuronidation via the UDP-glucuronosyltransferase (UGT) family of enzymes. To characterize the UGTs active against SAHA, homogenates from HEK293 cell lines overexpressing UGT wild-type or variant UGT were used. The hepatic UGTs 2B17 and 1A9 and the extrahepatic UGTs 1A8 and 1A10 exhibited the highest overall activity against SAHA as determined by V(max)/K(M) (16+/-6.5, 7.1+/-2.2, 33+/-6.3, and 24+/-2.4 nL x min(-1) x microg UGT protein(-1), respectively), with UGT2B17 exhibiting the lowest K(M) (300 micromol/L) against SAHA of any UGT in vitro. Whereas the UGT1A8p.Ala173Gly variant exhibited a 3-fold (P<0.005) decrease in glucuronidation activity against SAHA compared with wild-type UGT1A8, the UGT1A8p.Cys277Tyr variant exhibited no detectable glucuronidation activity; a similar lack of detectable glucuronidation activity was observed for the UGT1A10p.Gly139Lys variant. To analyze the effects of the UGT2B17 gene deletion variant (UGT2B17*2) on SAHA glucuronidation phenotype, human liver microsomes (HLM) were analyzed for glucuronidation activity against SAHA and compared with UGT2B17 genotype. HLM from subjects homozygous for UGT2B17*2 exhibited a 45% (P<0.01) decrease in glucuronidation activity and a 75% (P<0.002) increase in K(M) compared with HLMs from subjects homozygous for the wild-type UGT2B17*1 allele. Overall, these results suggest that several UGTs play an important role in the metabolism of SAHA and that UGT2B17-null individuals could potentially exhibit altered SAHA clearance rates with differences in overall response.
Asunto(s)
Glucuronosiltransferasa/metabolismo , Ácidos Hidroxámicos/farmacocinética , Línea Celular , Inhibidores Enzimáticos/farmacocinética , Glucuronosiltransferasa/genética , Humanos , Mutagénesis Sitio-Dirigida , Mutación Missense , Fenotipo , Polimorfismo Genético , VorinostatRESUMEN
Tobacco smoke contains high concentrations of reactive oxygen species (ROS) that can damage DNA, proteins, and lipids. Manganese superoxide dismutase (SOD2) catalyzes the dismutation of superoxide radicals into hydrogen peroxide and protects against oxidative stress in lung tissues. Three tagSNPs were identified in one block of high linkage disequilibrium that spans the entire SOD2 gene and 5-kb promoter region. These tagSNPs, representing four haplotypes (TAA, TCA, TCG, CCG), were genotyped in 372 lung cancer cases and 605 controls. There was no association between the haplotype frequencies and the overall lung cancer risk. The TCG haplotype (6% in controls) was significantly associated with a lower risk of lung cancer in light smokers (Asunto(s)
Adenocarcinoma/genética
, Carcinoma de Células Escamosas/genética
, Predisposición Genética a la Enfermedad
, Neoplasias Pulmonares/genética
, Fumar
, Superóxido Dismutasa/genética
, Adenocarcinoma/enzimología
, Adenocarcinoma/patología
, Anciano
, Carcinoma de Células Escamosas/enzimología
, Carcinoma de Células Escamosas/patología
, Femenino
, Frecuencia de los Genes
, Haplotipos
, Humanos
, Desequilibrio de Ligamiento
, Neoplasias Pulmonares/enzimología
, Neoplasias Pulmonares/patología
, Masculino
, Persona de Mediana Edad
, Polimorfismo de Nucleótido Simple
, Regiones Promotoras Genéticas
, Factores de Riesgo
, Superóxido Dismutasa/metabolismo
, Población Blanca
RESUMEN
Tamoxifen (TAM) is a selective estrogen receptor modulator widely used in the prevention and treatment of breast cancer. A major mode of metabolism of the major active metabolites of TAM, 4-OH-TAM and endoxifen, is by glucuronidation via the UDP-glucuronosyltransferase (UGT) family of enzymes. To examine whether polymorphisms in the UGT enzymes responsible for the glucuronidation of active TAM metabolites play an important role in interindividual differences in TAM metabolism, cell lines overexpressing wild-type or variant UGTs were examined for their activities against TAM metabolites in vitro. For variants of active extrahepatic UGTs, the UGT1A8(173Ala/277Tyr) variant exhibited no detectable glucuronidation activity against the trans isomers of either 4-OH-TAM or endoxifen. Little or no difference in TAM glucuronidating activity was observed for the UGT1A8(173Gly/277Cys) or UGT1A10(139Lys) variants compared with their wild-type counterparts. For active hepatic UGTs, the UGT2B7(268Tyr) variant exhibited significant (P < 0.01) 2- and 5-fold decreases in activity against the trans isomers of 4-OH-TAM and endoxifen, respectively, compared with wild-type UGT2B7(268His). In studies of 111 human liver microsomal specimens, the rate of O-glucuronidation against trans-4-OH-TAM and trans-endoxifen was 28% (P < 0.001) and 27% (P = 0.002) lower, respectively, in individuals homozygous for the UGT2B7 Tyr(268)Tyr genotype compared with subjects with the UGT2B7 His(268)His genotype, with a significant (P < 0.01) trend of decreasing activity against both substrates with increasing numbers of the UGT2B7(268His) allele. These results suggest that functional polymorphisms in TAM-metabolizing UGTs, including UGT2B7 and potentially UGT1A8, may be important in interindividual variability in TAM metabolism and response to TAM therapy.
Asunto(s)
Antagonistas de Estrógenos/metabolismo , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/fisiología , Tamoxifeno/metabolismo , Línea Celular , Citocromo P-450 CYP2D6/genética , Genotipo , Humanos , Tamoxifeno/análogos & derivadosRESUMEN
OBJECTIVE: To study the potential association between UDP-glucuronosyltransferase (UGT)2B10 genotypes and [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol] NNAL-N-glucuronidation activity in human liver microsomes (HLM) and to identify potential functional polymorphisms. METHODS: A total of 77 subjects were genotyped for three UGT2B10 tagging single nucleotide polymorphisms NNAL-N-glucuronidation activity in HLM was determined by high-pressure liquid chromatography and analyzed by UGT2B10 haplotypes. RESULTS: Four common UGT2B10 haplotypes (termed A through D) were identified. Haplotype C was found to be significantly (P<0.001) associated with lower NNAL-N-glucuronidation in HLM. A 1.8-fold and 12-fold reduction in NNAL-N-glucuronidation levels and a 1.7-fold and 11-fold reduction in the ratio of NNAL-N-Gluc: NNAL-O-Gluc, were observed in HLM from subjects with one and two copies of UGT2B10 haplotype C, respectively. A novel polymorphism resulting in an aspartic acid to tyrosine amino acid change at codon 67 of the UGT2B10 complementary DNA was identified exclusively in subjects with a haplotype C. Unlike the high activity observed in microsomes from HEK293 cells over expressing the wild-type UGT2B10(67Asp) variant, microsomes from HEK293 cells over expressing the UGT2B10(67Tyr) variant exhibited minimal glucuronide formation activity against NNAL or other tobacco-specific nitrosamines tested in vitro. CONCLUSIONS: The UGT2B10(67Tyr) variant corresponding to the UGT2B10 haplotype C is a functional single nucleotide polymorphism that may be responsible for inter individual variation in NNAL-N-glucuronidation activity and may increase susceptibility to smoking-related cancers.
Asunto(s)
Glucuronosiltransferasa/antagonistas & inhibidores , Glucuronosiltransferasa/genética , Mutación Missense , Nitrosaminas/metabolismo , Polimorfismo de Nucleótido Simple , Sustitución de Aminoácidos , Secuencia de Bases , Línea Celular , Cartilla de ADN/genética , ADN Complementario/genética , Glucuronosiltransferasa/metabolismo , Haplotipos , Humanos , Hígado/enzimología , Neoplasias/etiología , Neoplasias/genética , Neoplasias/metabolismo , Farmacogenética , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Fumar/efectos adversos , Fumar/genética , Fumar/metabolismo , Nicotiana/químicaRESUMEN
BACKGROUND: UDP-glucuronosyltransferase (UGT) 2B17 is a phase II metabolizing enzyme that mediates the glucuronidation of C(19) steroids. A deletion polymorphism in the UGT2B17 gene is associated with a substantial reduction in glucuronidation activity in vitro. METHODS: We examined the association between the UGT2B17 deletion polymorphism and the risk of incident prostate cancer in a population-based study from central Arkansas that included 411 Caucasian cases and 397 Caucasian controls. We developed a novel high-throughput procedure that uses real-time PCR and allelic discrimination for genotyping analysis. RESULTS: The prevalence of the UGT2B17 deletion [(0/0)] was 12% in the controls, which was consistent with previous population estimates and with Hardy Weinberg equilibrium. There was no association between the UGT2B17 deletion polymorphism and prostate cancer risk in unconditional logistic regression analysis. Compared to the wild-type group (+/+), the adjusted odds ratio (OR) was 0.89 (95% CI=0.55-1.45) for the homozygous deletion (0/0), and the OR was 0.99 (95% CI=0.73-1.35) for the heterozygote group (+/0). CONCLUSION: These findings show that the UGT2B17 deletion polymorphism is not associated with prostate cancer risk in Caucasians.