RESUMO
BACKGROUND AND AIMS: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes. METHODS: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted. RESULTS: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10-6, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis. CONCLUSIONS: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Modelos Genéticos , Alelos , Carcinogênese/genética , Estudos de Casos e Controles , Estudos de Coortes , Neoplasias Colorretais/epidemiologia , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , RNA-Seq , Fatores de Risco , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Non-supplemental carotenoids and retinol may potentiate antioxidant and anti-inflammatory mechanisms. Chronic intraprostatic inflammation is linked to prostate carcinogenesis. We investigated the association of circulating carotenoids and retinol with intraprostatic inflammation in benign tissue. We included 235 men from the Prostate Cancer Prevention Trial placebo arm who had a negative end-of-study biopsy, most (92.8%) done without clinical indication. α-carotene, ß-carotene, ß-cryptoxanthin, lycopene, and retinol were assessed by high-performance liquid chromatography using pooled year 1 and 4 serum. Presence and extent of intraprostatic inflammation in benign tissue was assessed in 3 (of 6-10) biopsy cores. Logistic (any core with inflammation vs none) and polytomous logistic (some or all cores with inflammation vs none) regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of intraprostatic inflammation by concentration tertile adjusting for age, race, prostate cancer family history, and serum cholesterol. None of the carotenoids or retinol was associated with intraprostatic inflammation, except ß-cryptoxanthin, which appeared to be positively associated with any core with inflammation [vs none, T2: OR (95% CI) = 2.67 (1.19, 5.99); T3: 1.80 (0.84, 3.82), P-trend = 0.12]. These findings suggest that common circulating carotenoids and retinol are not useful dietary intervention targets for preventing prostate cancer via modulating intraprostatic inflammation.
Assuntos
Neoplasias da Próstata , Retinoides , Biópsia , Carotenoides , Humanos , Inflamação , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/prevenção & controle , Vitamina ARESUMO
Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10-fold cross-validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47-4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65-0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans.
Assuntos
População Negra/estatística & dados numéricos , Predisposição Genética para Doença , Modelos Genéticos , Herança Multifatorial , Neoplasias da Próstata/epidemiologia , Fatores Etários , População Negra/genética , Estudos de Casos e Controles , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Neoplasias da Próstata/genéticaRESUMO
Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.
Assuntos
Neoplasias Colorretais/etiologia , Etanol/efeitos adversos , Idoso , Consumo de Bebidas Alcoólicas/efeitos adversos , Estudos de Casos e Controles , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND: Intraprostatic inflammation is an emerging prostate cancer risk factor. Estrogens are pro-inflammatory while androgens are anti-inflammatory. Thus, we investigated whether serum sex steroid hormone concentrations are associated with intraprostatic inflammation to inform mechanistic links among hormones, inflammation, and prostate cancer. METHODS: We conducted a cross-sectional study among 247 men in the placebo arm of the Prostate Cancer Prevention Trial who had a negative end-of-study biopsy, most (92.7%) performed without clinical indication per trial protocol. Serum estradiol, estrone, and testosterone were previously measured by immunoassay in pooled baseline and Year 3 serum. Free estradiol and free testosterone were calculated. Inflammation was visually assessed (median of three prostate biopsy cores per man). Polytomous or logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) of some or all cores inflamed (both vs none) or any core inflamed (vs none) by hormone tertile, adjusting for age, race, and family history. We evaluated effect modification by waist circumference and body mass index (BMI). RESULTS: In all, 51.4% had some and 26.3% had all cores inflamed. Free (P-trend = .11) but not total estradiol was suggestively inversely associated with all cores inflamed. In men with waist circumference greater than or equal to 102 cm (P-trend = .021) and BMI ≥ 27.09 kg/m2 (P-trend = .0037) free estradiol was inversely associated with any core inflamed. Estrone was inversely associated with all cores inflamed (T3: OR = 0.36, 95% CI 0.14-0.95, P-trend = .036). Total (T3: OR = 1.91, 95% CI 0.91-4.02, P-trend = .11) and free (T3: OR = 2.19, 95% CI 1.01-4.74, P-trend = .05) testosterone were positively associated with any core inflamed, especially free testosterone in men with waist circumference less than 102 cm (T3: OR = 3.51, 95% CI 1.03-12.11, P-trend = .05). CONCLUSIONS: In this first study in men without prostate cancer and irrespective of clinical indication for biopsy, contrary to the hypothesis, circulating estrogens appeared to be inversely associated, especially in heavy men, whereas androgens appeared to be positively associated with intraprostatic inflammation.
Assuntos
Hormônios Esteroides Gonadais/sangue , Prostatite/sangue , Idoso , Biópsia , Peso Corporal , Estudos Transversais , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Neoplasias da Próstata/prevenção & controle , Prostatite/patologia , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.
Assuntos
Adiposidade/genética , Obesidade/genética , Serina Endopeptidases/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Antropometria , População Negra/genética , Índice de Massa Corporal , Mapeamento Cromossômico , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Obesidade/patologia , Polimorfismo de Nucleotídeo Único , Relação Cintura-Quadril , População Branca/genéticaRESUMO
OBJECTIVE: Cross-sectional data indicate that systemic inflammation is important in oesophageal adenocarcinoma. We conducted a prospective study to assess whether prediagnostic circulating markers of inflammation were associated with oesophageal adenocarcinoma and to what extent they mediated associations of obesity and cigarette smoking with cancer risk. DESIGN: This nested case-control study included 296 oesophageal adenocarcinoma cases and 296 incidence density matched controls from seven prospective cohort studies. We quantitated 69 circulating inflammation markers using Luminex-based multiplex assays. Conditional logistic regression models estimated associations between inflammation markers and oesophageal adenocarcinoma, as well as direct and indirect effects of obesity and smoking on risk of malignancy. RESULTS: Soluble tumour necrosis factor receptor 2 (sTNFR2) (ORsquartile 4 vs 1=2.67, 95% CI 1.52 to 4.68) was significantly associated with oesophageal adenocarcinoma. Additional markers close to the adjusted significance threshold included C reactive protein, serum amyloid A, lipocalin-2, resistin, interleukin (IL) 3, IL17A, soluble IL-6 receptor and soluble vascular endothelial growth factor receptor 3. Adjustment for body mass index, waist circumference or smoking status slightly attenuated biomarker-cancer associations. Mediation analysis indicated that sTNFR2 may account for 33% (p=0.005) of the effect of waist circumference on oesophageal adenocarcinoma risk. Resistin, plasminogen activator inhibitor 1, C reactive protein and serum amyloid A were also identified as potential mediators of obesity-oesophageal adenocarcinoma associations. For smoking status, only plasminogen activator inhibitor 1 was a nominally statistically significant (p<0.05) mediator of cancer risk. CONCLUSION: This prospective study provides evidence of a link between systemic inflammation and oesophageal adenocarcinoma risk. In addition, this study provides the first evidence that indirect effects of excess adiposity and cigarette smoking, via systemic inflammation, increase the risk of oesophageal adenocarcinoma.
Assuntos
Adenocarcinoma/diagnóstico , Biomarcadores Tumorais/sangue , Detecção Precoce de Câncer , Neoplasias Esofágicas/diagnóstico , Mediadores da Inflamação/sangue , Adenocarcinoma/epidemiologia , Adenocarcinoma/metabolismo , Adenocarcinoma/cirurgia , Idoso , Índice de Massa Corporal , Consenso , Estudos Transversais , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/cirurgia , Feminino , Humanos , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Fumar/epidemiologiaAssuntos
Suplementos Nutricionais , Selênio , Vitamina E , Humanos , Selênio/administração & dosagem , Selênio/uso terapêutico , Vitamina E/administração & dosagem , Vitamina E/uso terapêutico , Masculino , Seguimentos , Taxa de Sobrevida , Fatores de Tempo , Neoplasias da Próstata/prevenção & controle , Neoplasias da Próstata/mortalidade , Antioxidantes/administração & dosagem , Antioxidantes/uso terapêuticoRESUMO
Substantial preclinical data suggest estrogen's carcinogenic role in prostate cancer development; however, epidemiological evidence based on circulating estrogen levels is largely null. Compared with circulating estrogen, the intraprostatic estrogen milieu may play a more important role in prostate carcinogenesis. Using a nested case-control design in the Prostate Cancer Prevention Trial (PCPT), we examined associations of genetic variants of genes that are involved in estrogen synthesis, metabolism and function with prostate cancer risk. A total of 25 potentially functional single nucleotide polymorphisms (SNPs) in 13 genes (PGR, ESR1, ESR2, CYP17A1, HSD17B1, CYP19A1, CYP1A1, CYP1B1, COMT, UGT1A6, UGT1A10, UGT2B7, UGT2B15) were examined in whites only. Controls (n = 1380) were frequency matched to cases on age, PCPT treatment arm, and family history (n = 1506). Logistic regression models adjusted for age and family history were used to estimate odds ratios (OR) and 95% confidence intervals (CI) separately in the placebo and finasteride arms. SNPs associated with prostate cancer risk differed by treatment arm. The associations appeared to be modified by circulating estrogen and androgen levels. CYP19A1 was the only gene harboring SNPs that were significantly associated with risk in both the placebo and finasteride arms. Haplotype analysis with all three CYP19A1 SNPs genotyped (rs700518, rs2445765, rs700519) showed that risk-allele haplotypes are associated with the increased prostate cancer risk in both arms when comparing with the non-risk allele haplotype. In conclusion, associations between SNPs in estrogen-related genes and prostate cancer risk are complex and may be modified by circulating hormone levels and finasteride treatment.
Assuntos
Aromatase/genética , Estrogênios/metabolismo , Predisposição Genética para Doença/genética , Neoplasias da Próstata/genética , Inibidores de 5-alfa Redutase/uso terapêutico , Idoso , Estudos de Casos e Controles , Finasterida/uso terapêutico , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/prevenção & controleRESUMO
Circadian genes have been considered as a possible biological mechanism for the observed relationship between circadian rhythm disruptions and increased risk of hormone-related cancers. In the current study, we investigated the relationship between circadian gene variants and prostate cancer risk and whether reducing bioavailable testosterone modifies the circadian genes-prostate cancer relationship. We conducted a nested case-control study among Caucasian men in the Prostate Cancer Prevention Trial (PCPT), a randomized placebo-controlled clinical trial to assess if finasteride (an androgen bioactivation inhibitor) could prevent prostate cancer. We evaluated the associations between 240 circadian gene variations and prostate cancer risk among 1092 biopsy-confirmed prostate cancer cases and 1089 biopsy-negative controls in the study (642 cases and 667 controls from the placebo group; 450 cases and 422 controls from the finasteride group), stratified by treatment group. Among men in the finasteride group, there were suggestive associations between NPAS2 variants and total prostate cancer risk, with one SNP remaining statistically significant after Bonferroni correction (rs746924, odds ratio [OR] = 1.5, P = 9.6 × 10-5 ). However, we found little evidence of increased prostate cancer risk (overall or by low/high grade) associated with circadian gene variations in men of the placebo group, suggesting potential modification of genetic effects by treatment. We did not find strong evidence that circadian gene variants influenced prostate cancer risk in men who were not on finasteride treatment. There were suggestive associations between NPAS2 variants and prostate cancer risk among men using finasteride, which warrants further investigations.
Assuntos
Inibidores de 5-alfa Redutase/uso terapêutico , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Finasterida/uso terapêutico , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Neoplasias da Próstata/prevenção & controle , Idoso , Estudos de Casos e Controles , Relógios Circadianos , Humanos , Masculino , Pessoa de Meia-Idade , Próstata/efeitos dos fármacos , Próstata/enzimologia , Próstata/metabolismo , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/epidemiologia , Fatores de RiscoRESUMO
BACKGROUND: We reported that some, but not all single nucleotide polymorphisms (SNPs) in select immune response genes are associated with prostate cancer, but not individually with the prevalence of intraprostatic inflammation in the Prostate Cancer Prevention Trial (PCPT) placebo arm. Here, we investigated whether these same SNPs are associated with risk of lower- and higher-grade prostate cancer in men randomized to finasteride, and with prevalence of intraprostatic inflammation among controls. Methods A total of 16 candidate SNPs in IL1ß, IL2, IL4, IL6, IL8, IL10, IL12(p40), IFNG, MSR1, RNASEL, TLR4, and TNFA and 7 tagSNPs in IL10 were genotyped in 625 white prostate cancer cases, and 532 white controls negative for cancer on an end-of-study biopsy nested in the PCPT finasteride arm. We used logistic regression to estimate log-additive odds ratios (OR) and 95% confidence intervals (CI) adjusting for age and family history. RESULTS: Minor alleles of rs2243250 (T) in IL4 (OR = 1.46, 95% CI 1.03-2.08, P-trend = 0.03), rs1800896 (G) in IL10 (OR = 0.77, 95% CI 0.61-0.96, P-trend = 0.02), rs2430561 (A) in IFNG (OR = 1.33, 95% CI 1.02-1.74; P-trend = 0.04), rs3747531 (C) in MSR1 (OR = 0.55, 95% CI 0.32-0.95; P-trend = 0.03), and possibly rs4073 (A) in IL8 (OR = 0.81, 95% CI 0.64-1.01, P-trend = 0.06) were associated with higher- (Gleason 7-10; N = 222), but not lower- (Gleason 2-6; N = 380) grade prostate cancer. In men with low PSA (<2 ng/mL), these higher-grade disease associations were attenuated and/or no longer significant, whereas associations with higher-grade disease were apparent for minor alleles of rs1800795 (C: OR = 0.70, 95% CI 0.51-0.94, P-trend = 0.02) and rs1800797 (A: OR = 0.72, 95% CI 0.53-0.98, P-trend = 0.04) in IL6. While some IL10 tagSNPs were associated with lower- and higher-grade prostate cancer, distributions of IL10 haplotypes did not differ, except possibly between higher-grade cases and controls among those with low PSA (P = 0.07). We did not observe an association between the studied SNPs and intraprostatic inflammation in the controls. CONCLUSION: In the PCPT finasteride arm, variation in genes involved in the immune response, including possibly IL8 and IL10 as in the placebo arm, may be associated with prostate cancer, especially higher-grade disease, but not with intraprostatic inflammation. We cannot rule out PSA-associated detection bias or chance due to multiple testing.
Assuntos
Finasterida/administração & dosagem , Inflamação , Interleucina-10/genética , Interleucina-8/genética , Próstata , Neoplasias da Próstata , Idoso , Biópsia/métodos , Estudos de Associação Genética , Humanos , Inflamação/genética , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Polimorfismo de Nucleotídeo Único , Próstata/imunologia , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/prevenção & controle , Agentes Urológicos/administração & dosagemAssuntos
Finasterida/uso terapêutico , Neoplasias da Próstata/mortalidade , Inibidores de 5-alfa Redutase/efeitos adversos , Inibidores de 5-alfa Redutase/uso terapêutico , Detecção Precoce de Câncer , Finasterida/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/induzido quimicamente , Neoplasias da Próstata/prevenção & controleRESUMO
Reports relating meat intake to prostate cancer risk are inconsistent. Associations between these dietary factors and prostate cancer were examined in a consortium of 15 cohort studies. During follow-up, 52,683 incident prostate cancer cases, including 4,924 advanced cases, were identified among 842,149 men. Cox proportional hazard models were used to calculate study-specific relative risks (RR) and then pooled using random effects models. Results do not support a substantial effect of total red, unprocessed red and processed meat for all prostate cancer outcomes, except for a modest positive association for tumors identified as advanced stage at diagnosis (advanced(r)). For seafood, no substantial effect was observed for prostate cancer regardless of stage or grade. Poultry intake was inversely associated with risk of advanced and fatal cancers (pooled multivariable RR [MVRR], 95% confidence interval, comparing ≥ 45 vs. <5 g/day: advanced 0.83, 0.70-0.99; trend test p value 0.29), fatal, 0.69, 0.59-0.82, trend test p value 0.16). Participants who ate ≥ 25 versus <5 g/day of eggs (1 egg â¼ 50 g) had a significant 14% increased risk of advanced and fatal cancers (advanced 1.14, 1.01-1.28, trend test p value 0.01; fatal 1.14, 1.00-1.30, trend test p value 0.01). When associations were analyzed separately by geographical region (North America vs. other continents), positive associations between unprocessed red meat and egg intake, and inverse associations between poultry intake and advanced, advanced(r) and fatal cancers were limited to North American studies. However, differences were only statistically significant for eggs. Observed differences in associations by geographical region warrant further investigation.
Assuntos
Dieta , Ovos , Carne , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/etiologia , Alimentos Marinhos , Estudos de Coortes , Humanos , Incidência , Masculino , Razão de Chances , Estudos Prospectivos , RiscoRESUMO
BACKGROUND: Intraprostatic inflammation has been associated with lower urinary tract symptom (LUTS) progression. However, prior studies used tissue removed for clinical indications, potentially skewing inflammation extent or biasing the association. We, therefore, evaluated inflammation and LUTS incidence and progression in men who underwent biopsy of the prostate peripheral zone irrespective of indication. MATERIALS AND METHODS: We developed nested case-control sets in men in the placebo arm of the Prostate Cancer Prevention Trial who were free of clinical BPH and had a protocol-directed year 7 biopsy. Cases had baseline IPSS <15 and year 7 IPSS of 8-14 (low, N = 47), 15-19 (incident moderate, N = 42), or ≥20 (incident high, N = 44). Controls had baseline and year 7 IPSS <8 (N = 41). For progression from IPSS <8, cases had baseline to year 7 IPSS slope >75th percentile (N = 46) and controls had a slope <25th percentile (N = 45). For progression from IPSS = 8-14, cases had a slope >75th percentile (N = 46) and controls had a slope <25th percentile (N = 46). We reviewed three H&E-stained biopsy cores per man to determine prevalence of ≥1 core with inflammation and mean extent (%) of tissue area with inflammation. RESULTS: Inflammation prevalence in low cases (64%) was similar to controls (66%), but higher in moderate (69%) and high (73%) cases (P-trend = 0.4). Extent did not differ across LUTS categories (P-trend = 0.5). For progression from IPSS < 8, prevalence (65%, P = 0.9) and extent (2.5%, P = 0.8) in cases did not differ from controls (64%, 2.7%). For progression from IPSS 8-14, prevalence in cases (52%) was lower than in controls (78%, P = 0.009), while extent was higher in cases (5.3%) than controls (3.6%), especially in men with ≥1 core with inflammation (10.1% versus 4.6%, P = 0.06). CONCLUSION: Peripheral zone intraprostatic inflammation is not strongly associated with LUTS incidence or progression. Prostate 76:1399-1408, 2016. © 2016 Wiley Periodicals, Inc.
Assuntos
Inflamação/patologia , Sintomas do Trato Urinário Inferior/patologia , Próstata/patologia , Idoso , Biópsia com Agulha de Grande Calibre , Estudos de Casos e Controles , Progressão da Doença , Humanos , Incidência , MasculinoRESUMO
BACKGROUND: We previously reported that both intraprostatic inflammation and SNPs in genes involved in the immune response are associated with prostate cancer risk and disease grade. In the present study, we evaluated the association between these SNPs and intraprostatic inflammation in men without a prostate cancer diagnosis. METHODS: Included in this cross-sectional study were 205 white controls from a case-control study nested in the placebo arm of the Prostate Cancer Prevention Trial. We analyzed inflammation data from the review of H&E-stained prostate tissue sections from biopsies performed per protocol at the end of the trial irrespective of clinical indication, and data for 16 SNPs in key genes involved in the immune response (IL1ß, IL2, IL4, IL6, IL8, IL10, IL12(p40), IFNG, MSR1, RNASEL, TLR4, TNFA; 7 tagSNPs in IL10). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between carrying at least one minor allele and having at least one biopsy core (of a mean of three reviewed) with inflammation. RESULTS: None of the SNPs evaluated was statistically significantly associated with having at least one core with inflammation. However, possible inverse associations were present for carrying the minor allele of rs2069762 (G) in IL2 (OR = 0.51, 95%CI 0.25-1.02); carrying two copies of the minor allele of rs1800871 (T) of IL10 (OR = 0.29, 95%CI 0.08-1.00); and carrying the minor allele of rs486907 (A) in RNASEL (OR = 0.52, 95%CI 0.26-1.06). After creating a genetic risk score from the three SNPs possibly associated with inflammation, the odds of inflammation increased with increasing number of risk alleles (P-trend = 0.008). CONCLUSION: While our findings do not generally support a cross-sectional link between individual SNPs in key genes involved in the immune response and intraprostatic inflammation in men without a prostate cancer diagnosis, they do suggest that some of these variants when in combination may be associated with intraprostatic inflammation in benign tissue.
Assuntos
Endorribonucleases , Inflamação , Interleucina-10 , Interleucina-2 , Próstata/patologia , Neoplasias da Próstata , Idoso , Estudos de Casos e Controles , Estudos Transversais , Endorribonucleases/genética , Endorribonucleases/imunologia , Predisposição Genética para Doença , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Masculino , Polimorfismo de Nucleotídeo Único , Próstata/imunologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/prevenção & controleRESUMO
BACKGROUND: While family history (FH) has been widely used to provide risk information, it captures only a small proportion of subjects with higher genetic susceptibility. Our objective is to assess whether a genetic risk score (GRS) calculated from prostate cancer (PCa) risk-associated single nucleotide polymorphisms (SNPs) can supplement FH for more effective risk stratification for PCa screening decision-making. METHODS: A GRS was calculated based on 29 PCa risk-associated SNPs for 4,528 men of European descent in the placebo arm of the Prostate Cancer Prevention Trial (PCPT). At study entry, participants were free of PCa diagnosis. Performance of FH and GRS were measured by observed detection rate of PCa and high-grade PCa (Gleason score ≥7) during the 7-year study. RESULTS: GRS was a significant predictor of PCa in men with or without a positive FH (P = 1.18 × 10(-4) and P = 4.50 × 10(-16) , respectively). Using FH alone, as expected, the 17% of men who were FH+ had a PCa detection rate that was significantly higher (29.02%) than FH- men (23.43%, P = 0.001). When both FH+ or GRS >1.4 are considered, more than twice as many men (36%) can be classified as higher risk, as evidenced by a significantly higher PCa detection rate (30.98%) than in the remaining men (20.61%, P = 5.30 × 10(-15) ). If targeting only FH+ men, four out of five PCa cases would go undetected, as would a similarly large fraction (â¼80%) of high-grade PCa cases. In comparison, if targeting FH+ or GRS >1.4 men, almost half of all PCa cases would be detected, including 45% of high-grade PCa cases. CONCLUSIONS: A prostate cancer GRS can supplement family history to better identify higher risk men for targeted intervention. Prostate 76:1120-1129, 2016. © 2016 Wiley Periodicals, Inc.
Assuntos
Predisposição Genética para Doença , Neoplasias da Próstata/genética , Neoplasias da Próstata/prevenção & controle , Humanos , Masculino , Anamnese , Pessoa de Meia-Idade , Gradação de Tumores , Placebos , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/patologia , Medição de Risco/métodos , Fatores de Risco , População BrancaRESUMO
BACKGROUND: Prostate cancer is highly influenced by androgens and genes. The authors investigated whether genetic polymorphisms along the androgen biosynthesis and metabolism pathways are associated with androgen concentrations or with the risk of prostate cancer or high-grade disease from finasteride treatment. METHODS: A nested case-control study from the Prostate Cancer Prevention Trial using data from men who had biopsy-proven prostate cancer (cases) and a group of biopsy-negative, frequency-matched controls was conducted to investigate the association of 51 single nucleotide polymorphisms (SNPs) in 12 genes of the androgen pathway with overall (total), low-grade, and high-grade prostate cancer incidence and serum hormone concentrations. RESULTS: There were significant associations of genetic polymorphisms in steroid 5α-reductase 1 (SRD5A1) (reference SNPs: rs3736316, rs3822430, rs1560149, rs248797, and rs472402) and SRD5A2 (rs2300700) with the risk of high-grade prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial; 2 SNPs were significantly associated with an increased risk (SRD5A1 rs472402 [odds ratio, 1.70; 95% confidence interval, 1.05-2.75; Ptrend = .03] and SRD5A2 rs2300700 [odds ratio, 1.94; 95% confidence interval, 1.19-3.18; Ptrend = .01]). Eleven SNPs in SRD5A1, SRD5A2, cytochrome P450 family 1, subfamily B, polypeptide 1 (CYP1B1), and CYP3A4 were associated with modifying the mean concentrations of serum androgen and sex hormone-binding globulin; and 2 SNPs (SRD5A1 rs824811 and CYP1B1 rs10012; Ptrend < .05) consistently and significantly altered all androgen concentrations. Several SNPs (SRD5A1 rs3822430, SRD5A2 rs2300700, CYP3A43 rs800672, and CYP19 rs700519; Ptrend < .05) were significantly associated with both circulating hormone levels and prostate cancer risk. CONCLUSIONS: Germline genetic variations of androgen-related pathway genes are associated with serum androgen concentrations and the risk of prostate cancer. Further studies to examine the functional consequence of novel causal variants are warranted. Cancer 2016;122:2332-2340. © 2016 American Cancer Society.
Assuntos
Androgênios/metabolismo , Predisposição Genética para Doença , Polimorfismo Genético , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/metabolismo , Alelos , Androgênios/sangue , Biomarcadores , Estudos de Casos e Controles , Ensaios Clínicos como Assunto , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Redes e Vias Metabólicas/genética , Gradação de Tumores , Razão de Chances , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/diagnósticoRESUMO
BACKGROUND: In the Prostate Cancer Prevention Trial (PCPT), finasteride significantly reduced the risk of prostate cancer but was associated with an increased risk of high-grade disease. With up to 18 years of follow-up, we analyzed rates of survival among all study participants and among those with prostate cancer. METHODS: We collected data on the incidence of prostate cancer among PCPT participants for an additional year after our first report was published in 2003 and searched the Social Security Death Index to assess survival status through October 31, 2011. RESULTS: Among 18,880 eligible men who underwent randomization, prostate cancer was diagnosed in 989 of 9423 (10.5%) in the finasteride group and 1412 of 9457 (14.9%) in the placebo group (relative risk in the finasteride group, 0.70; 95% confidence interval [CI], 0.65 to 0.76; P<0.001). Of the men who were evaluated, 333 (3.5%) in the finasteride group and 286 (3.0%) in the placebo group had high-grade cancer (Gleason score, 7 to 10) (relative risk, 1.17; 95% CI, 1.00 to 1.37; P=0.05). Of the men who died, 2538 were in the finasteride group and 2496 were in the placebo group, for 15-year survival rates of 78.0% and 78.2%, respectively. The unadjusted hazard ratio for death in the finasteride group was 1.02 (95% CI, 0.97 to 1.08; P=0.46). Ten-year survival rates were 83.0% in the finasteride group and 80.9% in the placebo group for men with low-grade prostate cancer and 73.0% and 73.6%, respectively, for those with high-grade prostate cancer. CONCLUSIONS: Finasteride reduced the risk of prostate cancer by about one third. High-grade prostate cancer was more common in the finasteride group than in the placebo group, but after 18 years of follow-up, there was no significant between-group difference in the rates of overall survival or survival after the diagnosis of prostate cancer. (Funded by the National Cancer Institute.).
Assuntos
Inibidores de 5-alfa Redutase/uso terapêutico , Finasterida/uso terapêutico , Neoplasias da Próstata/prevenção & controle , Seguimentos , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Gradação de Tumores , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Risco , Taxa de SobrevidaRESUMO
BACKGROUND: Compelling and long-standing data suggest that androgens play an important role in the development of both normal prostate epithelium and prostate cancer. Although testosterone administration can induce prostate cancer (PCA) in laboratory animals, serum-based epidemiologic studies examining androgens in humans have not consistently supported a role for androgens in prostate carcinogenesis. We examined whether pre-diagnostic serum androgens were associated with PCA risk in the placebo arm of the Prostate Cancer Prevention Trial. METHODS: In this nested case-control study, cases (n = 1,032) were primarily local-stage, biopsy-detected cancers, and controls (n = 1,025) were biopsy-confirmed to be PCA-free. Pre-diagnostic serum androgens (total testosterone, 3α-androstanediol glucuronide, free testosterone), estrogen-to-testosterone ratio, and sex hormone-binding globulin (SHBG) concentrations were measured in pooled (baseline and year 3) blood samples. RESULTS: We found no significant associations between serum androgens, estrogen-to-testosterone ratios, or SHBG and risk of total, low (Gleason <7) or high-grade (Gleason 7-10) PCA. CONCLUSION: Much remains to be learned about the role of androgens in prostate carcinogenesis. Further research is needed to evaluate the role of androgens, timing of exposure, genetic modulators of androgen metabolism, or environmental exposures that may affect androgen influence on prostate carcinogenesis.