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1.
J Natl Cancer Inst ; 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35512400

RESUMO

BACKGROUND: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. METHODS: We conducted a genome-wide gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen-only, and combined estrogen-progestogen therapy with CRC risk, among 28,486 postmenopausal women (11,519 cases and 16,967 controls) from 38 studies, using logistic regression, two-step method, and 2- or 3-degree-of-freedom (d.f.) joint test. A set-based score test was applied for rare genetic variants. RESULTS: The use of any MHT, estrogen-only and estrogen-progestogen were associated with a reduced CRC risk [odds ratio (OR) with 95% confidence interval (95% CI) of 0.71 (0.64-0.78), 0.65 (0.53-0.79), and 0.73 (0.59-0.90), respectively]. The two-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was significantly reduced in women with the GG genotype [0.68 (0.64-0.72)] but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-d.f. joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing ORs of 0.78 (0.70-0.87) for TT, 0.68 (0.63-0.73) for TC, and 0.66 (0.60-0.74) for CC genotypes. In addition, five genes in rare variant analysis showed suggestive interactions with MHT (two-sided P < 1.2x10-4). CONCLUSION: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.

2.
Occup Environ Med ; 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35504721

RESUMO

OBJECTIVES: There has been concern over the possible risk of autoimmune diseases from exposure to trichloroethylene (TCE), an industrial solvent and common pollutant near hazardous waste sites. Studies of TCE-exposed lupus-prone mouse strains have reported increases in serum antinuclear antibodies (ANAs), a marker of autoimmunity, and autoimmune pathologic changes, while epidemiologic studies have provided limited support for an association between TCE exposure and scleroderma. To investigate exposure-related biologic evidence of autoimmunity in humans, we measured ANA levels in sera from a cross-sectional study of TCE-exposed (n=80) and TCE-unexposed (n=96) workers in Guangdong, China. METHODS: Full-shift personal air exposure measurements for TCE were taken prior to blood collection. Serum ANAs were detected by immunofluorescence on HEp-2 cells. We calculated ORs and 95% CI relating levels of TCE exposure (categorised using tertiles as cut-points) and ANA positivity (1+ intensity at 1:320 dilution) using multivariable logistic regression. RESULTS: Samples from 16 of 176 participants were ANA-positive. We found higher levels of TCE exposure (concentrations>17.27 ppm) to be associated with an elevated odds of ANA positivity (OR 4.7, 95% CI 1.3 to 16.8) compared with unexposed controls. This association remained after excluding two subjects with diagnosed autoimmune disease (OR 4.5, 95% CI 1.2 to 16.2). We did not observe an association with ANAs at lower exposure levels. CONCLUSIONS: Our findings, to our knowledge the first direct human evidence of an association between TCE exposure and systemic autoimmunity, provide biologic plausibility to epidemiologic evidence relating TCE and autoimmune disease.

3.
Cancer Epidemiol Biomarkers Prev ; 31(5): 1077-1089, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-35438744

RESUMO

BACKGROUND: Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer. METHODS: Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers (>28 g/day) with light-to-moderate drinkers (1-28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models. RESULTS: For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 > 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose-response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06-1.17; OR for AA genotype = 1.22; 95% CI, 1.14-1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif. CONCLUSIONS: Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region. IMPACT: The study identifies multifaceted evidence of a possible functional effect for rs1318920.


Assuntos
Neoplasias Colorretais , Estudo de Associação Genômica Ampla , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/genética , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco
4.
Artigo em Inglês | MEDLINE | ID: mdl-35152271

RESUMO

BACKGROUND: Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets. METHODS: In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry-the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured. RESULTS: The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively. CONCLUSIONS: We demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

5.
JNCI Cancer Spectr ; 6(1)2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35112050

RESUMO

Background: Although obesity is a known risk factor, the impact of weight change on colorectal adenoma risk is less clear and could have important implications in disease prevention. We prospectively evaluated weight change in adulthood and incident colorectal adenoma. Methods: We assessed weight change during early-late (age 20 years to baseline, ie, ages 55-74 years), early-middle (20-50 years), and middle-late (50 years-baseline) adulthood using self-reported weight data in relation to incident distal adenoma in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (cases = 1053; controls = 16 576). For each period, we defined stable weight as greater than -0.5 kg to less than or equal to 1 kg/5 years, weight loss as less than or equal to -0.5 kg/5 years, and weight gain as greater than 1-2, greater than 2-3, or greater than 3 kg/5 years. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression; all tests were 2-sided. Results: Compared with stable weight, weight loss during early-late adulthood was associated with reduced adenoma risk (OR = 0.54, 95% CI = 0.34 to 0.86), particularly among those who were overweight or obese at age 20 years (OR = 0.39, 95% CI = 0.18 to 0.84). Results were similar for early-middle adulthood but less pronounced for middle-late adulthood. Weight gain greater than 3 kg/5 years during early-late adulthood was associated with increased risk (OR = 1.30, 95% CI = 1.07 to 1.58, P trend < .001). Findings appeared stronger among men (OR for >3 kg/5 years = 1.41, 95% CI = 1.11 to 1.80) than women (OR = 1.09, 95% CI = 0.79 to 1.50, P interaction = .21). Conclusions: Weight loss in adulthood was associated with reduced adenoma risk, particularly for those who were overweight or obese, whereas weight gain greater than 3 kg/5 years increased risk. Findings underscore the importance of healthy weight maintenance throughout adulthood in preventing colorectal adenoma.


Assuntos
Adenoma/etiologia , Neoplasias Colorretais/etiologia , Ganho de Peso , Perda de Peso , Adulto , Idoso , Estudos de Casos e Controles , Intervalos de Confiança , Feminino , Humanos , Modelos Logísticos , Neoplasias Pulmonares , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Razão de Chances , Neoplasias Ovarianas , Sobrepeso/complicações , Neoplasias da Próstata , Fatores de Risco , Adulto Jovem
6.
Eur Urol ; 81(5): 458-462, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35031163

RESUMO

A rare African ancestry-specific germline deletion variant in HOXB13 (X285K, rs77179853) was recently reported in Martinican men with early-onset prostate cancer. Given the role of HOXB13 germline variation in prostate cancer, we investigated the association between HOXB13 X285K and prostate cancer risk in a large sample of 22 361 African ancestry men, including 11 688 prostate cancer cases. The risk allele was present only in men of West African ancestry, with an allele frequency in men that ranged from 0.40% in Ghana and 0.31% in Nigeria to 0% in Uganda and South Africa, with a range of frequencies in men with admixed African ancestry from North America and Europe (0-0.26%). HOXB13 X285K was associated with 2.4-fold increased odds of prostate cancer (95% confidence interval [CI] = 1.5-3.9, p = 2 × 10-4), with greater risk observed for more aggressive and advanced disease (Gleason ≥8: odds ratio [OR] = 4.7, 95% CI = 2.3-9.5, p = 2 × 10-5; stage T3/T4: OR = 4.5, 95% CI = 2.0-10.0, p = 2 × 10-4; metastatic disease: OR = 5.1, 95% CI = 1.9-13.7, p = 0.001). We estimated that the allele arose in West Africa 1500-4600 yr ago. Further analysis is needed to understand how the HOXB13 X285K variant impacts the HOXB13 protein and function in the prostate. Understanding who carries this mutation may inform prostate cancer screening in men of West African ancestry. PATIENT SUMMARY: A rare African ancestry-specific germline deletion in HOXB13, found only in men of West African ancestry, was reported to be associated with an increased risk of overall and advanced prostate cancer. Understanding who carries this mutation may help inform screening for prostate cancer in men of West African ancestry.


Assuntos
Detecção Precoce de Câncer , Neoplasias da Próstata , Estudos de Casos e Controles , Predisposição Genética para Doença , Células Germinativas/patologia , Mutação em Linhagem Germinativa , Proteínas de Homeodomínio/genética , Humanos , Masculino , Antígeno Prostático Específico/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia
7.
Int J Cancer ; 150(9): 1447-1454, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-34888857

RESUMO

Elevated blood levels of C-reactive protein (CRP) have been linked to colorectal cancer (CRC) survival. We evaluated genetic variants associated with CRP levels and their interactions with sex and lifestyle factors in association with CRC-specific mortality. Our study included 16 142 CRC cases from the International Survival Analysis in Colorectal Cancer Consortium. We identified 618 common single nucleotide polymorphisms (SNPs) associated with CRP levels from the NHGRI-EBI GWAS Catalog. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between SNPs and CRC-specific mortality adjusting for age, sex, genotyping platform/study and principal components. We investigated their interactions with sex and lifestyle factors using likelihood ratio tests. Of 5472 (33.9%) deaths accrued over up to 10 years of follow-up, 3547 (64.8%) were due to CRC. No variants were associated with CRC-specific mortality after multiple comparison correction. We observed strong evidence of interaction between variant rs1933736 at FRK gene and sex in relation to CRC-specific mortality (corrected Pinteraction  = .0004); women had higher CRC-specific mortality associated with the minor allele (HR = 1.11, 95% CI = 1.04-1.19) whereas an inverse association was observed for men (HR = 0.88, 95% CI = 0.82-0.94). There was no evidence of interactions between CRP-associated SNPs and alcohol, obesity or smoking. Our study observed a significant interaction between sex and a CRP-associated variant in relation to CRC-specific mortality. Future replication of this association and functional annotation of the variant are needed.


Assuntos
Proteína C-Reativa , Neoplasias Colorretais , Proteína C-Reativa/análise , Proteína C-Reativa/genética , Feminino , Humanos , Estilo de Vida , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Análise de Sobrevida
8.
Cancer Epidemiol Biomarkers Prev ; 31(1): 210-220, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34737207

RESUMO

BACKGROUND: Fusobacterium nucleatum (F. nucleatum) activates oncogenic signaling pathways and induces inflammation to promote colorectal carcinogenesis. METHODS: We characterized F. nucleatum and its subspecies in colorectal tumors and examined associations with tumor characteristics and colorectal cancer-specific survival. We conducted deep sequencing of nusA, nusG, and bacterial 16s rRNA genes in tumors from 1,994 patients with colorectal cancer and assessed associations between F. nucleatum presence and clinical characteristics, colorectal cancer-specific mortality, and somatic mutations. RESULTS: F. nucleatum, which was present in 10.3% of tumors, was detected in a higher proportion of right-sided and advanced-stage tumors, particularly subspecies animalis. Presence of F. nucleatum was associated with higher colorectal cancer-specific mortality (HR, 1.97; P = 0.0004). This association was restricted to nonhypermutated, microsatellite-stable tumors (HR, 2.13; P = 0.0002) and those who received chemotherapy [HR, 1.92; confidence interval (CI), 1.07-3.45; P = 0.029). Only F. nucleatum subspecies animalis, the main subspecies detected (65.8%), was associated with colorectal cancer-specific mortality (HR, 2.16; P = 0.0016), subspecies vincentii and nucleatum were not (HR, 1.07; P = 0.86). Additional adjustment for tumor stage suggests that the effect of F. nucleatum on mortality is partly driven by a stage shift. Presence of F. nucleatum was associated with microsatellite instable tumors, tumors with POLE exonuclease domain mutations, and ERBB3 mutations, and suggestively associated with TP53 mutations. CONCLUSIONS: F. nucleatum, and particularly subspecies animalis, was associated with a higher colorectal cancer-specific mortality and specific somatic mutated genes. IMPACT: Our findings identify the F. nucleatum subspecies animalis as negatively impacting colorectal cancer mortality, which may occur through a stage shift and its effect on chemoresistance.


Assuntos
Neoplasias Colorretais , Fusobacterium nucleatum , Carcinogênese , Neoplasias Colorretais/genética , Humanos , RNA Ribossômico 16S
9.
Genome Biol ; 23(1): 13, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34996498

RESUMO

BACKGROUND: Genome-wide association study (GWAS) single nucleotide polymorphisms (SNPs) are known to preferentially co-locate to active regulatory elements in tissues and cell types relevant to disease aetiology. Further characterisation of associated cell type-specific regulation can broaden our understanding of how GWAS signals may contribute to disease risk. RESULTS: To gain insight into potential functional mechanisms underlying GWAS associations, we developed FORGE2 ( https://forge2.altiusinstitute.org/ ), which is an updated version of the FORGE web tool. FORGE2 uses an expanded atlas of cell type-specific regulatory element annotations, including DNase I hotspots, five histone mark categories and 15 hidden Markov model (HMM) chromatin states, to identify tissue- and cell type-specific signals. An analysis of 3,604 GWAS from the NHGRI-EBI GWAS catalogue yielded at least one significant disease/trait-tissue association for 2,057 GWAS, including > 400 associations specific to epigenomic marks in immune tissues and cell types, > 30 associations specific to heart tissue, and > 60 associations specific to brain tissue, highlighting the key potential of tissue- and cell type-specific regulatory elements. Importantly, we demonstrate that FORGE2 analysis can separate previously observed accessible chromatin enrichments into different chromatin states, such as enhancers or active transcription start sites, providing a greater understanding of underlying regulatory mechanisms. Interestingly, tissue-specific enrichments for repressive chromatin states and histone marks were also detected, suggesting a role for tissue-specific repressed regions in GWAS-mediated disease aetiology. CONCLUSION: In summary, we demonstrate that FORGE2 has the potential to uncover previously unreported disease-tissue associations and identify new candidate mechanisms. FORGE2 is a transparent, user-friendly web tool for the integrative analysis of loci discovered from GWAS.


Assuntos
Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Epigenômica , Predisposição Genética para Doença , Humanos , Fenótipo , Sequências Reguladoras de Ácido Nucleico
10.
JNCI Cancer Spectr ; 5(5)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34738070

RESUMO

Background: Smoking has been associated with colorectal cancer (CRC) incidence and mortality in previous studies, but current evidence on smoking in association with survival after CRC diagnosis is limited. Methods: We pooled data from 12 345 patients with stage I-IV CRC from 11 epidemiologic studies in the International Survival Analysis in Colorectal Cancer Consortium. Cox proportional hazards regression models were used to evaluate the associations of prediagnostic smoking behavior with overall, CRC-specific, and non-CRC-specific survival. Results: Among 12 345 patients with CRC, 4379 (35.5%) died (2515 from CRC) over a median follow-up time of 7.5 years. Smoking was strongly associated with worse survival in stage I-III patients, whereas no association was observed among stage IV patients. Among stage I-III patients, clear dose-response relationships with all survival outcomes were seen for current smokers. For example, current smokers with 40 or more pack-years had statistically significantly worse overall, CRC-specific, and non-CRC-specific survival compared with never smokers (hazard ratio [HR] =1.94, 95% confidence interval [CI] =1.68 to 2.25; HR = 1.41, 95% CI = 1.12 to 1.78; and HR = 2.67, 95% CI = 2.19 to 3.26, respectively). Similar associations with all survival outcomes were observed for former smokers who had quit for less than 10 years, but only a weak association with non-CRC-specific survival was seen among former smokers who had quit for more than 10 years. Conclusions: This large consortium of CRC patient studies provides compelling evidence that smoking is strongly associated with worse survival of stage I-III CRC patients in a clear dose-response manner. The detrimental effect of smoking was primarily related to noncolorectal cancer events, but current heavy smoking also showed an association with CRC-specific survival.


Assuntos
Neoplasias Colorretais/mortalidade , Fumar/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Intervalos de Confiança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Tempo
11.
JNCI Cancer Spectr ; 5(4)2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34377935

RESUMO

Background: Smoking is associated with colorectal cancer (CRC) risk. Previous studies suggested this association may be restricted to certain molecular subtypes of CRC, but large-scale comprehensive analysis is lacking. Methods: A total of 9789 CRC cases and 11 231 controls of European ancestry from 11 observational studies were included. We harmonized smoking variables across studies and derived sex study-specific quartiles of pack-years of smoking for analysis. Four somatic colorectal tumor markers were assessed individually and in combination, including BRAF mutation, KRAS mutation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status. A multinomial logistic regression analysis was used to assess the association between smoking and risk of CRC subtypes by molecular characteristics, adjusting for age, sex, and study. All statistical tests were 2-sided and adjusted for Bonferroni correction. Results: Heavier smoking was associated with higher risk of CRC overall and stratified by individual markers (P trend < .001). The associations differed statistically significantly between all molecular subtypes, which was the most statistically significant for CIMP and BRAF. Compared with never-smokers, smokers in the fourth quartile of pack-years had a 90% higher risk of CIMP-positive CRC (odds ratio = 1.90, 95% confidence interval = 1.60 to 2.26) but only 35% higher risk for CIMP-negative CRC (odds ratio = 1.35, 95% confidence interval = 1.22 to 1.49; P difference = 2.1 x 10-6). The association was also stronger in tumors that were CIMP positive, MSI high, or KRAS wild type when combined (P difference < .001). Conclusion: Smoking was associated with differential risk of CRC subtypes defined by molecular characteristics. Heavier smokers had particularly higher risk of CRC subtypes that were CIMP positive and MSI high in combination, suggesting that smoking may be involved in the development of colorectal tumors via the serrated pathway.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Instabilidade de Microssatélites , Mutação , Fumar/efeitos adversos , Fatores Etários , Estudos de Casos e Controles , Ilhas de CpG/genética , Feminino , Genes ras/genética , Marcadores Genéticos/genética , Humanos , Modelos Logísticos , Masculino , Metilação , não Fumantes , Estudos Observacionais como Assunto , Fenótipo , Proteínas Proto-Oncogênicas B-raf/genética , Fatores Sexuais , Fumantes
12.
Am J Clin Nutr ; 114(4): 1408-1417, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34258619

RESUMO

BACKGROUND: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis. OBJECTIVES: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC. METHODS: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs. RESULTS: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association. CONCLUSIONS: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.


Assuntos
Adenocarcinoma/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Hepcidinas/metabolismo , Ferro/metabolismo , Neoplasias Pancreáticas/metabolismo , Idoso , Estudos de Casos e Controles , Feminino , Genótipo , Hepcidinas/genética , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
13.
Prostate ; 81(10): 683-693, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33956343

RESUMO

BACKGROUND: Inflammation and one of its mediators, NF-kappa B (NFκB), have been implicated in prostate cancer carcinogenesis. We assessed whether germline polymorphisms associated with NFκB are associated with the risk of developing lethal disease (metastases or death from prostate cancer). METHODS: Using a Bayesian approach leveraging NFκB biology with integration of publicly available datasets we used a previously defined genome-wide functional association network specific to NFκB and lethal prostate cancer. A dense-module-searching method identified modules enriched with significant genes from a genome-wide association study (GWAS) study in a discovery data set, Physicians' Health Study and Health Professionals Follow-up Study (PHS/HPFS). The top 48 candidate single nucleotide polymorphisms (SNPs) from the dense-module-searching method were then assessed in an independent prostate cancer cohort and the one SNP reproducibly associated with lethality was tested in a third cohort. Logistic regression models evaluated the association between each SNP and lethal prostate cancer. The candidate SNP was assessed for association with lethal prostate cancer in 6 of 28 studies in the prostate cancer association group to investigate cancer associated alterations in the genome (PRACTICAL) Consortium where there was some medical record review for death ascertainment which also had SNP data from the ONCOARRAY platform. All men self-identified as Caucasian. RESULTS: The rs1910301 SNP which was reproducibly associated with lethal disease was nominally associated with lethal disease (odds ratio [OR] = 1.40; p = .02) in the discovery cohort and the minor allele was also associated with lethal disease in two independent cohorts (OR = 1.35; p = .04 and OR = 1.35; p = .07). Fixed effects meta-analysis of all three cohorts found an association: OR = 1.37 (95% confidence interval [CI]: 1.15-1.62, p = .0003). This SNP is in the promoter region of FRAS1, a gene involved in epidermal-basement membrane adhesion and is present at a higher frequency in men with African ancestry. No association was found in the subset of studies from the PRACTICAL consortium studies which had a total of 106 deaths out total of 3263 patients and a median follow-up of 4.4 years. CONCLUSIONS: Through its connection with the NFκB pathway, a candidate SNP with a higher frequency in men of African ancestry without cancer was found to be associated with lethal prostate cancer across three well-annotated independent cohorts of Caucasian men.


Assuntos
Proteínas da Matriz Extracelular/genética , Estudos de Associação Genética/métodos , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Neoplasias da Próstata/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/diagnóstico
14.
Cancer ; 127(17): 3145-3155, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-33974712

RESUMO

BACKGROUND: Studying the differential impact of aspirin and other nonsteroidal anti-inflammatory drugs across the stages of colorectal neoplasia from early adenoma to cancer is critical for understanding the benefits of these widely used drugs. METHODS: With 13 years of follow-up, the authors prospectively evaluated the association between aspirin and ibuprofen use and incident distal adenoma (1221 cases), recurrent adenoma (862 cases), and incident colorectal cancer (CRC; 2826 cases) among men and women in the population-based Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. With multivariable-adjusted models, odds ratio (ORs) and 95% confidence intervals (CIs) for adenoma incidence and recurrence and hazard ratios (HRs) and 95% CIs for incident CRC were determined. RESULTS: The authors observed a significantly reduced risk of incident adenoma with ibuprofen use (≥30 vs <4 pills per month: OR, 0.76 [95% CI, 0.60-0.95]; Ptrend = .04), particularly advanced adenoma (OR, 0.48 [95% CI, 0.28-0.83]; Ptrend = .005). Among those with a previous adenoma detected through screening, aspirin use was associated with a decreased risk of advanced recurrent adenoma (≥30 vs <4 pills per month: OR, 0.56 [95% CI, 0.36-0.87]; Ptrend = 0.006). Both aspirin (HR, 0.88 [95% CI, 0.81-0.96]; Ptrend <.0001) and ibuprofen use (HR, 0.81 [95% CI, 0.70-0.93); Ptrend = 0.003) ≥30 versus <4 pills per month were significantly associated with reduced CRC risk. CONCLUSIONS: In this large prospective study with long-term follow-up, a beneficial role for not only aspirin, but also ibuprofen, in preventing advanced adenoma and curbing progression to recurrence and cancer among older adults was observed.


Assuntos
Adenoma , Neoplasias Colorretais , Adenoma/diagnóstico , Adenoma/epidemiologia , Adenoma/prevenção & controle , Idoso , Aspirina/uso terapêutico , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/prevenção & controle , Detecção Precoce de Câncer , Feminino , Humanos , Ibuprofeno/uso terapêutico , Incidência , Masculino , Estudos Prospectivos
15.
Cancer Epidemiol Biomarkers Prev ; 30(7): 1349-1358, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33972368

RESUMO

BACKGROUND: A positive association between circulating C-reactive protein (CRP) and colorectal cancer survival was reported in observational studies, which are susceptible to unmeasured confounding and reverse causality. We used a Mendelian randomization approach to evaluate the association between genetically predicted CRP concentrations and colorectal cancer-specific survival. METHODS: We used individual-level data for 16,918 eligible colorectal cancer cases of European ancestry from 15 studies within the International Survival Analysis of Colorectal Cancer Consortium. We calculated a genetic-risk score based on 52 CRP-associated genetic variants identified from genome-wide association studies. Because of the non-collapsibility of hazard ratios from Cox proportional hazards models, we used the additive hazards model to calculate hazard differences (HD) and 95% confidence intervals (CI) for the association between genetically predicted CRP concentrations and colorectal cancer-specific survival, overall and by stage at diagnosis and tumor location. Analyses were adjusted for age at diagnosis, sex, body mass index, genotyping platform, study, and principal components. RESULTS: Of the 5,395 (32%) deaths accrued over up to 10 years of follow-up, 3,808 (23%) were due to colorectal cancer. Genetically predicted CRP concentration was not associated with colorectal cancer-specific survival (HD, -1.15; 95% CI, -2.76 to 0.47 per 100,000 person-years; P = 0.16). Similarly, no associations were observed in subgroup analyses by stage at diagnosis or tumor location. CONCLUSIONS: Despite adequate power to detect moderate associations, our results did not support a causal effect of circulating CRP concentrations on colorectal cancer-specific survival. IMPACT: Future research evaluating genetically determined levels of other circulating inflammatory biomarkers (i.e., IL6) with colorectal cancer survival outcomes is needed.


Assuntos
Proteína C-Reativa/análise , Neoplasias Colorretais/mortalidade , Idoso , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Feminino , Seguimentos , Variação Genética , Humanos , Masculino , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Fatores de Risco
16.
Genome Med ; 13(1): 74, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931109

RESUMO

BACKGROUND: DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach. METHODS: The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses. RESULTS: We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development. CONCLUSIONS: We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.


Assuntos
Epigênese Genética , Epigenômica , Estudo de Associação Genômica Ampla , Rim/metabolismo , Locos de Características Quantitativas , Característica Quantitativa Herdável , /genética , Ilhas de CpG , Metilação de DNA , Epigenômica/métodos , Regulação da Expressão Gênica , Variação Genética , Genética Populacional , Taxa de Filtração Glomerular , Humanos , Testes de Função Renal , Fenótipo
17.
Am J Hum Genet ; 108(4): 564-582, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33713608

RESUMO

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.


Assuntos
/genética , Estatura/genética , Estudo de Associação Genômica Ampla , África/etnologia , Afro-Americanos/genética , Europa (Continente)/etnologia , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética
18.
Cancer Epidemiol Biomarkers Prev ; 30(6): 1279-1282, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33737297

RESUMO

BACKGROUND: The association between prediagnostic antibody responses to Fusobacterium nucleatum (F. nucleatum) and subsequent risk of colorectal cancer is not established. METHODS: We conducted a nested case-control study of 8,126 participants in a consortium of 10 prospective cohorts in the United States. RESULTS: Higher seroprevalence of any F. nucleatum antibody was observed among non-White participants (51.1%) compared with White participants (31.2%). We did not find any statistically significant association between seropositivity to any of the eight F. nucleatum proteins and colorectal cancer risk. CONCLUSIONS: Prediagnostic antibody responses to F. nucleatum proteins were not associated with the risk of colorectal cancer. IMPACT: Future studies may consider a more specific detection of the immunoglobulin isotypes or focus on examining F. nucleatum in stool or tissue samples.


Assuntos
Anticorpos Antibacterianos/sangue , Neoplasias Colorretais/epidemiologia , Fusobacterium nucleatum/imunologia , Microbioma Gastrointestinal/imunologia , Idoso , Anticorpos Antibacterianos/imunologia , Proteínas de Bactérias/imunologia , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Medição de Risco/estatística & dados numéricos , Estudos Soroepidemiológicos , Estados Unidos
19.
Am J Clin Nutr ; 113(6): 1490-1502, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33740060

RESUMO

BACKGROUND: The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited. OBJECTIVES: To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (ß-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR). METHODS: Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions. RESULTS: Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of ß-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk. CONCLUSIONS: These results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Análise da Randomização Mendeliana , Micronutrientes/administração & dosagem , Estudos de Casos e Controles , Suplementos Nutricionais , Humanos , Fatores de Risco , Selênio/sangue , Vitamina B 12/sangue
20.
Int J Epidemiol ; 50(4): 1325-1334, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-33748835

RESUMO

BACKGROUND: Epidemiological studies have demonstrated a positive association between chronic lymphocytic leukaemia (CLL) and non-melanoma skin cancer (NMSC). We hypothesized that shared genetic risk factors between CLL and NMSC could contribute to the association observed between these diseases. METHODS: We examined the association between (i) established NMSC susceptibility loci and CLL risk in a meta-analysis including 3100 CLL cases and 7667 controls and (ii) established CLL loci and NMSC risk in a study of 4242 basal cell carcinoma (BCC) cases, 825 squamous cell carcinoma (SCC) cases and 12802 controls. Polygenic risk scores (PRS) for CLL, BCC and SCC were constructed using established loci. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Higher CLL-PRS was associated with increased BCC risk (OR4th-quartile-vs-1st-quartile = 1.13, 95% CI: 1.02-1.24, Ptrend = 0.009), even after removing the shared 6p25.3 locus. No association was observed with BCC-PRS and CLL risk (Ptrend = 0.68). These findings support a contributory role for CLL in BCC risk, but not for BCC in CLL risk. Increased CLL risk was observed with higher SCC-PRS (OR4th-quartile-vs-1st-quartile = 1.22, 95% CI: 1.08-1.38, Ptrend = 1.36 × 10-5), which was driven by shared genetic susceptibility at the 6p25.3 locus. CONCLUSION: These findings highlight the role of pleiotropy regarding the pathogenesis of CLL and NMSC and shows that a single pleiotropic locus, 6p25.3, drives the observed association between genetic susceptibility to SCC and increased CLL risk. The study also provides evidence that genetic susceptibility for CLL increases BCC risk.


Assuntos
Carcinoma Basocelular , Carcinoma de Células Escamosas , Leucemia Linfocítica Crônica de Células B , Neoplasias Cutâneas , Carcinoma Basocelular/epidemiologia , Carcinoma Basocelular/genética , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/genética , Humanos , Leucemia Linfocítica Crônica de Células B/epidemiologia , Leucemia Linfocítica Crônica de Células B/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/genética
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