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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.
Artigo em Inglês | MEDLINE | ID: mdl-35437568

RESUMO

BACKGROUND: Obesity is a risk factor for endometrial cancer but whether metabolic dysfunction is associated with endometrial cancer independent of body size is not known. METHODS: The association of metabolically-defined body size phenotypes with endometrial cancer risk was investigated in a nested case-control study (817 cases/ 817 controls) within the European Prospective Investigation into Cancer and Nutrition (EPIC). Concentrations of C-peptide were used to define metabolically healthy (MH; <1st tertile) and metabolically unhealthy (MU; >=1st tertile) status among the control participants. These metabolic health definitions were combined with normal weight (NW; Body Mass Index (BMI)<25kg/m2 or Waist Circumference (WC)<80cm or Waist-to-Hip Ratio (WHR)<0.8) and overweight (OW; BMI>=25kg/m2 or WC>=80cm or WHR>=0.8) status, generating four phenotype groups for each anthropometric measure: (1)MH/NW, (2)MH/OW (3)MU/NW and (4)MU/OW. RESULTS: In a multivariable-adjusted conditional logistic regression model, compared with MH/NW individuals, endometrial cancer risk was higher among those classified as MU/NW (OR/WC=1.48; 95%CI 1.05-2.10 and OR/WHR=1.68; 95%CI 1.21-2.35) and MU/OW (OR/BMI=2.38, 95%CI 1.73-3.27; OR/WC=2.69, 95%CI 1.92-3.77 and OR/WHR=1.83, 95%CI 1.32-2.54). MH/OW individuals were also at increased endometrial cancer risk compared to MH/NW individuals (OR/WC=1.94, 95%CI 1.24-3.04). CONCLUSIONS: Women with metabolic dysfunction appear to have higher risk of endometrial cancer regardless of their body size. However, overweight status raises endometrial cancer risk even among women with lower insulin levels, suggesting that obesity-related pathways are relevant for the development of this cancer beyond insulin. IMPACT: Classifying women by metabolic health may be of greater utility in identifying those at higher risk for endometrial cancer than anthropometry per se.

3.
J Natl Cancer Inst ; 2022 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-35438160

RESUMO

It is unclear if body weight in early life affects cancer risk independently of adult body weight. To investigate this question for six obesity-related cancers, we performed univariable and multivariable analyses using i) Mendelian randomization (MR) analysis and ii) longitudinal analyses in prospective cohorts. Both the MR and longitudinal analyses indicated that larger body size at age 10 was associated with higher risk of endometrial (ORMR=1.61, 95%CI = 1.23-2.11) and kidney cancer (ORMR=1.40, 95%CI = 1.09-1.80). These associations were attenuated after accounting for adult body size in both the MR and cohort analyses. Early life BMI was not consistently associated with the other investigated cancers. The lack of clear independent risk associations suggests that early life BMI influences endometrial and kidney cancer risk mainly through pathways that are common with adult BMI.

4.
Cardiovasc Diabetol ; 21(1): 54, 2022 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-35436955

RESUMO

BACKGROUND: Mildly elevated bilirubin, a by-product of hemoglobin breakdown, might mitigate cardiometabolic risk factors including adiposity, dyslipidemia, and high blood pressure (BP). We investigated the cross-sectional relationship between (total) bilirubin and baseline cardiometabolic risk factors in 467,519 UK Biobank study participants. METHODS: We used multivariable-adjusted linear regression to estimate associations between bilirubin levels and risk factors of cardiometabolic diseases including body mass index (BMI), waist and hip circumferences (WC, HC), waist-to-hip ratio (WHR), fat mass (FM), and trunk FM, and the blood lipids: apolipoprotein A-I (apoA-I), apolipoprotein B (apoB), apoB/apoA-I, lipoprotein (a), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), LDL/HDL, TC/HDL, triglycerides (TG). Log-transformed bilirubin was modelled with restricted cubic splines and predicted mean values with 99% confidence intervals (CI) for each risk marker were estimated, separately. Second, we applied principal component analysis (PCA) for dimension reduction to in turn six anthropometric traits (height, weight, BMI, WC, HC, and WHR) and all above lipids. Last, we estimated associations (99%CI) between bilirubin and three components of the metabolic syndrome, i.e. WC, TG, and BP using logistic regression. RESULTS: After multivariable adjustments, higher levels of bilirubin were inversely associated with indicators of general adiposity (BMI and FM) and of body fat distribution (WC, HC, WHR, and trunk FM) in both men and women. For example, women with mildly elevated bilirubin (95th percentile equal to 15.0 µmol/L), compared to women with low bilirubin (5th percentile equal to 4.5 µmol/L), had on average a 2.0 kg/m2 (99% CI 1.9-2.1) lower BMI. Inverse associations were also observed with dyslipidemia among men and women. For example, mildly elevated bilirubin among men (95th percentile equal to 19.4 µmol/L) compared to low levels of bilirubin (5th percentile equal to 5.5 µmol/L) were associated with approx. 0.55 mmol/L (99% CI 0.53-0.56) lower TG levels, with similar inverse associations among women. Multiple-trait analyses using PCA confirmed single-trait analyses. Men and women with mildly elevated bilirubin levels ≥ 17.1 µmol/L, compared to low-normal bilirubin < 10 µmol/L had 13% (99% CI 8%-18%) and 11% (99% CI 4%-17%) lower odds of exceeding systolic BP levels of ≥ 130 mm Hg, respectively. CONCLUSIONS: Higher levels of bilirubin were inversely associated with cardiometabolic risk factors including adiposity, dyslipidemia, and hypertension.


Assuntos
Dislipidemias , Hipertensão , Apolipoproteína A-I , Apolipoproteínas B , Bilirrubina , Bancos de Espécimes Biológicos , Índice de Massa Corporal , HDL-Colesterol , Estudos Transversais , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Feminino , Humanos , Lipídeos , Masculino , Obesidade , Fatores de Risco , Triglicerídeos , Reino Unido/epidemiologia
5.
Int J Cancer ; 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35383926

RESUMO

Diabetes is an established risk factor for colorectal cancer. However, colorectal cancer is a heterogeneous disease and it is not well understood whether diabetes is more strongly associated with some tumor molecular subtypes than others. A better understanding of the association between diabetes and colorectal cancer according to molecular subtypes could provide important insights into the biology of this association. We used data on lifestyle and clinical characteristics from the Colorectal Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), including 9756 colorectal cancer cases (with tumor marker data) and 9985 controls, to evaluate associations between reported diabetes and risk of colorectal cancer according to molecular subtypes. Tumor markers included BRAF and KRAS mutations, microsatellite instability and CpG island methylator phenotype. In the multinomial logistic regression model, comparing colorectal cancer cases to cancer-free controls, diabetes was positively associated with colorectal cancer regardless of subtype. The highest OR estimate was found for BRAF-mutated colorectal cancer, n = 1086 (ORfully adj : 1.67, 95% confidence intervals [CI]: 1.36-2.05), with an attenuated association observed between diabetes and colorectal cancer without BRAF-mutations, n = 7959 (ORfully adj : 1.33, 95% CI: 1.19-1.48). In the case only analysis, BRAF-mutation was differentially associated with diabetes (Pdifference  = .03). For the other markers, associations with diabetes were similar across tumor subtypes. In conclusion, our study confirms the established association between diabetes and colorectal cancer risk, and suggests that it particularly increases the risk of BRAF-mutated tumors.

7.
BMC Med ; 20(1): 3, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-35012533

RESUMO

BACKGROUND: Epidemiological and experimental evidence has linked chronic inflammation to cancer aetiology. It is unclear whether associations for specific inflammatory biomarkers are causal or due to bias. In order to examine whether altered genetically predicted concentration of circulating cytokines are associated with cancer development, we performed a two-sample Mendelian randomisation (MR) analysis. METHODS: Up to 31,112 individuals of European descent were included in genome-wide association study (GWAS) meta-analyses of 47 circulating cytokines. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene (cis), were used as instrumental variables. Inverse-variance weighted MR was used as the primary analysis, and the MR assumptions were evaluated in sensitivity and colocalization analyses and a false discovery rate (FDR) correction for multiple comparisons was applied. Corresponding germline GWAS summary data for five cancer outcomes (breast, endometrial, lung, ovarian, and prostate), and their subtypes were selected from the largest cancer-specific GWASs available (cases ranging from 12,906 for endometrial to 133,384 for breast cancer). RESULTS: There was evidence of inverse associations of macrophage migration inhibitory factor with breast cancer (OR per SD = 0.88, 95% CI 0.83 to 0.94), interleukin-1 receptor antagonist with endometrial cancer (0.86, 0.80 to 0.93), interleukin-18 with lung cancer (0.87, 0.81 to 0.93), and beta-chemokine-RANTES with ovarian cancer (0.70, 0.57 to 0.85) and positive associations of monokine induced by gamma interferon with endometrial cancer (3.73, 1.86 to 7.47) and cutaneous T-cell attracting chemokine with lung cancer (1.51, 1.22 to 1.87). These associations were similar in sensitivity analyses and supported in colocalization analyses. CONCLUSIONS: Our study adds to current knowledge on the role of specific inflammatory biomarker pathways in cancer aetiology. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for cancer prevention.


Assuntos
Análise da Randomização Mendeliana , Neoplasias Ovarianas , Citocinas/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Metanálise como Assunto , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco
8.
Cancer Epidemiol Biomarkers Prev ; 31(4): 793-803, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35086823

RESUMO

BACKGROUND: Endogenous sex hormones may contribute to higher colorectal cancer incidence rates in men compared with women, but despite an increased number of studies, clear evidence is lacking. METHODS: We conducted a comprehensive nested case-control study of circulating concentrations of sex hormones, sex hormone precursors, and sex hormone binding globulin (SHBG) in relation to subsequent colon cancer risk in European men. Concentrations were measured using liquid LC/MS-MS in prospectively collected plasma samples from 690 cases and 690 matched controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Northern Sweden Health and Disease Study (NSHDS) cohorts. Multivariable conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). In addition, we conducted a meta-analysis of previous studies on men. RESULTS: Circulating levels of testosterone (OR, 0.68; 95% CI, 0.51-0.89) and SHBG (OR, 0.77; 95% CI, 0.62-0.96) were inversely associated with colon cancer risk. For free testosterone, there was a nonsignificant inverse association (OR, 0.83; 95% CI, 0.58-1.18). In a dose-response meta-analysis of endogenous sex hormone levels, inverse associations with colorectal/colon cancer risk were found for testosterone [relative risks (RR) per 100 ng/dL = 0.98; 95% CI, 0.96-1.00; I2 = 22%] and free testosterone (RR per 1 ng/dL = 0.98; 95% CI, 0.95-1.00; I2 = 0%). CONCLUSIONS: Our results provide suggestive evidence for the association between testosterone, SHBG, and male colon cancer development. IMPACT: Additional support for the involvement of sex hormones in male colon cancer.


Assuntos
Neoplasias do Colo , Globulina de Ligação a Hormônio Sexual , Estudos de Casos e Controles , Neoplasias do Colo/epidemiologia , Estradiol , Feminino , Hormônios Esteroides Gonadais , Humanos , Modelos Logísticos , Masculino , Estudos Prospectivos , Fatores de Risco , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona
9.
J Natl Cancer Inst ; 114(5): 740-752, 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35048991

RESUMO

BACKGROUND: Glycemic traits-such as hyperinsulinemia, hyperglycemia, and type 2 diabetes-have been associated with higher colorectal cancer risk in observational studies; however, causality of these associations is uncertain. We used Mendelian randomization (MR) to estimate the causal effects of fasting insulin, 2-hour glucose, fasting glucose, glycated hemoglobin (HbA1c), and type 2 diabetes with colorectal cancer. METHODS: Genome-wide association study summary data were used to identify genetic variants associated with circulating levels of fasting insulin (n = 34), 2-hour glucose (n = 13), fasting glucose (n = 70), HbA1c (n = 221), and type 2 diabetes (n = 268). Using 2-sample MR, we examined these variants in relation to colorectal cancer risk (48 214 case patient and 64 159 control patients). RESULTS: In inverse-variance models, higher fasting insulin levels increased colorectal cancer risk (odds ratio [OR] per 1-SD = 1.65, 95% confidence interval [CI] = 1.15 to 2.36). We found no evidence of any effect of 2-hour glucose (OR per 1-SD = 1.02, 95% CI = 0.86 to 1.21) or fasting glucose (OR per 1-SD = 1.04, 95% CI = 0.88 to 1.23) concentrations on colorectal cancer risk. Genetic liability to type 2 diabetes (OR per 1-unit increase in log odds = 1.04, 95% CI = 1.01 to 1.07) and higher HbA1c levels (OR per 1-SD = 1.09, 95% CI = 1.00 to 1.19) increased colorectal cancer risk, although these findings may have been biased by pleiotropy. Higher HbA1c concentrations increased rectal cancer risk in men (OR per 1-SD = 1.21, 95% CI = 1.05 to 1.40), but not in women. CONCLUSIONS: Our results support a causal effect of higher fasting insulin, but not glucose traits or type 2 diabetes, on increased colorectal cancer risk. This suggests that pharmacological or lifestyle interventions that lower circulating insulin levels may be beneficial in preventing colorectal tumorigenesis.


Assuntos
Neoplasias Colorretais , Diabetes Mellitus Tipo 2 , Hiperinsulinismo , Glicemia/análise , Glicemia/genética , Neoplasias Colorretais/complicações , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Estudo de Associação Genômica Ampla , Hemoglobina A Glicada/análise , Humanos , Hiperinsulinismo/complicações , Hiperinsulinismo/genética , Insulina , Masculino , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Fatores de Risco
10.
J Natl Cancer Inst ; 114(4): 528-539, 2022 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-35026030

RESUMO

BACKGROUND: The incidence of colorectal cancer (CRC) among individuals aged younger than 50 years has been increasing. As screening guidelines lower the recommended age of screening initiation, concerns including the burden on screening capacity and costs have been recognized, suggesting that an individualized approach may be warranted. We developed risk prediction models for early-onset CRC that incorporate an environmental risk score (ERS), including 16 lifestyle and environmental factors, and a polygenic risk score (PRS) of 141 variants. METHODS: Relying on risk score weights for ERS and PRS derived from studies of CRC at all ages, we evaluated risks for early-onset CRC in 3486 cases and 3890 controls aged younger than 50 years. Relative and absolute risks for early-onset CRC were assessed according to values of the ERS and PRS. The discriminatory performance of these scores was estimated using the covariate-adjusted area under the receiver operating characteristic curve. RESULTS: Increasing values of ERS and PRS were associated with increasing relative risks for early-onset CRC (odds ratio per SD of ERS = 1.14, 95% confidence interval [CI] = 1.08 to 1.20; odds ratio per SD of PRS = 1.59, 95% CI = 1.51 to 1.68), both contributing to case-control discrimination (area under the curve = 0.631, 95% CI = 0.615 to 0.647). Based on absolute risks, we can expect 26 excess cases per 10 000 men and 21 per 10 000 women among those scoring at the 90th percentile for both risk scores. CONCLUSIONS: Personal risk scores have the potential to identify individuals at differential relative and absolute risk for early-onset CRC. Improved discrimination may aid in targeted CRC screening of younger, high-risk individuals, potentially improving outcomes.


Assuntos
Neoplasias Colorretais , Detecção Precoce de Câncer , Idoso , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco
11.
Clin Gastroenterol Hepatol ; 20(5): e1061-e1082, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-33279777

RESUMO

BACKGROUND & AIMS: Colorectal cancer risk can be lowered by adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guidelines. We derived metabolic signatures of adherence to these guidelines and tested their associations with colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort. METHODS: Scores reflecting adherence to the WCRF/AICR recommendations (scale, 1-5) were calculated from participant data on weight maintenance, physical activity, diet, and alcohol among a discovery set of 5738 cancer-free European Prospective Investigation into Cancer and Nutrition participants with metabolomics data. Partial least-squares regression was used to derive fatty acid and endogenous metabolite signatures of the WCRF/AICR score in this group. In an independent set of 1608 colorectal cancer cases and matched controls, odds ratios (ORs) and 95% CIs were calculated for colorectal cancer risk per unit increase in WCRF/AICR score and per the corresponding change in metabolic signatures using multivariable conditional logistic regression. RESULTS: Higher WCRF/AICR scores were characterized by metabolic signatures of increased odd-chain fatty acids, serine, glycine, and specific phosphatidylcholines. Signatures were inversely associated more strongly with colorectal cancer risk (fatty acids: OR, 0.51 per unit increase; 95% CI, 0.29-0.90; endogenous metabolites: OR, 0.62 per unit change; 95% CI, 0.50-0.78) than the WCRF/AICR score (OR, 0.93 per unit change; 95% CI, 0.86-1.00) overall. Signature associations were stronger in male compared with female participants. CONCLUSIONS: Metabolite profiles reflecting adherence to WCRF/AICR guidelines and additional lifestyle or biological risk factors were associated with colorectal cancer. Measuring a specific panel of metabolites representative of a healthy or unhealthy lifestyle may identify strata of the population at higher risk of colorectal cancer.


Assuntos
Neoplasias Colorretais , Estilo de Vida Saudável , Estudos de Coortes , Neoplasias Colorretais/epidemiologia , Dieta/efeitos adversos , Ácidos Graxos , Feminino , Humanos , Masculino , Estudos Prospectivos , Fatores de Risco
12.
JNCI Cancer Spectr ; 5(6)2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34805742

RESUMO

Background: Observational studies have consistently reported that postmenopausal hormone therapy use is associated with lower colon cancer risk, but epidemiologic studies examining the associations between circulating concentrations of endogenous estrogens and colorectal cancer have reported inconsistent results. Methods: We investigated the associations between circulating concentrations of estrone, estradiol, free estradiol, testosterone, free testosterone, androstenedione, dehydroepiandrosterone (DHEA), progesterone, and sex hormone-binding globulin (SHBG) with colon cancer risk in a nested case-control study of 1028 postmenopausal European women (512 colon cancer cases, 516 matched controls) who were noncurrent users of exogenous hormones at blood collection. Multivariable conditional logistic regression models were used to compute odds ratios and 95% confidence intervals to evaluate the association between circulating sex hormones and colon cancer risk. We also conducted a dose-response meta-analysis of prospective studies of circulating estrone and estradiol with colorectal, colon, and rectal cancer risk in postmenopausal women. All statistical tests were 2-sided. Results: In the multivariable model, a nonstatistically significantly positive relationship was found between circulating estrone and colon cancer risk (odds ratio per log2 1-unit increment = 1.17 [95% confidence interval = 1.00 to 1.38]; odds ratioquartile4-quartile1 = 1.33 [95% confidence interval = 0.89 to 1.97], P trend = .20). Circulating concentrations of estradiol, free estradiol, testosterone, free testosterone, androstenedione, DHEA, progesterone, and SHBG were not associated with colon cancer risk. In the dose-response meta-analysis, no clear evidence of associations were found between circulating estradiol and estrone concentrations with colorectal, colon, and rectal cancer risk. Conclusion: Our observational and meta-analysis results do not support an association between circulating concentrations of endogenous sex hormones and colon or rectal cancer in postmenopausal women.


Assuntos
Neoplasias do Colo/etiologia , Hormônios Esteroides Gonadais/sangue , Pós-Menopausa/sangue , Neoplasias Retais/etiologia , Androstenodiona/sangue , Estudos de Casos e Controles , Intervalos de Confiança , Sulfato de Desidroepiandrosterona/sangue , Estradiol/sangue , Estrogênios/sangue , Estrona/sangue , Europa (Continente) , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Progesterona/sangue , Estudos Prospectivos , Globulina de Ligação a Hormônio Sexual/análise , Testosterona/sangue
13.
Artigo em Inglês | MEDLINE | ID: mdl-34687971

RESUMO

BACKGROUND & AIMS: Gastrointestinal cancer risk is influenced by the presence of metabolic syndrome (MetS). However, previous epidemiologic studies lacked full serological biomarker data for the classification of MetS, and the interaction of MetS with germline cancer risk variants is unknown. METHODS: We investigated the associations between MetS and gastrointestinal cancer risk (overall, colorectal, pancreatic, esophageal adenocarcinoma, esophageal squamous cell carcinoma, stomach cardia, stomach non-cardia, hepatocellular carcinoma, and intrahepatic bile duct cancer) in 366,016 United Kingdom Biobank participants with comprehensive serum biomarker and genotype data. MetS status was determined by 3 different definitions at baseline, and, in 15,152 participants, at a repeat assessment after a median of 4.3 years of follow-up. Multivariable hazard ratios and 95% confidence intervals for cancer outcomes were estimated using Cox proportional hazards models. Analyses stratified by polygenic risk score were conducted for colorectal and pancreatic cancers. RESULTS: During a median follow-up of 7.1 years, 4238 incident cases of a gastrointestinal cancer occurred. MetS at baseline was associated with higher risk of overall gastrointestinal cancer by any definition (hazard ratio, 1.21; 95% confidence interval, 1.13-1.29, harmonized definition). MetS was associated with increased risks of colorectal cancer, colon cancer, rectal cancer, hepatocellular carcinoma, pancreatic cancer in women, and esophageal adenocarcinoma in men. Associations for colorectal cancer and pancreatic cancer did not differ by polygenic risk score strata (P-heterogeneity 0.70 and 0.69, respectively), and 80% of participants with MetS at baseline retained this status at the repeat assessment. CONCLUSIONS: These findings underscore the importance of maintaining good metabolic health in reducing the burden of gastrointestinal cancers, irrespective of genetic predisposition.

14.
Nutrients ; 13(9)2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34579050

RESUMO

Approximately 4% of cancers worldwide are caused by alcohol consumption. Drinking alcohol increases the risk of several cancer types, including cancers of the upper aerodigestive tract, liver, colorectum, and breast. In this review, we summarise the epidemiological evidence on alcohol and cancer risk and the mechanistic evidence of alcohol-mediated carcinogenesis. There are several mechanistic pathways by which the consumption of alcohol, as ethanol, is known to cause cancer, though some are still not fully understood. Ethanol's metabolite acetaldehyde can cause DNA damage and block DNA synthesis and repair, whilst both ethanol and acetaldehyde can disrupt DNA methylation. Ethanol can also induce inflammation and oxidative stress leading to lipid peroxidation and further DNA damage. One-carbon metabolism and folate levels are also impaired by ethanol. Other known mechanisms are discussed. Further understanding of the carcinogenic properties of alcohol and its metabolites will inform future research, but there is already a need for comprehensive alcohol control and cancer prevention strategies to reduce the burden of cancer attributable to alcohol.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Transtornos Induzidos por Álcool/metabolismo , Carcinogênese/induzido quimicamente , Etanol/efeitos adversos , Neoplasias/induzido quimicamente , Acetaldeído/efeitos adversos , Dano ao DNA/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Humanos
15.
Br J Cancer ; 125(9): 1308-1317, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34363033

RESUMO

BACKGROUND: Dysregulation of endocrine pathways related to steroid and growth hormones may modify endometrial cancer risk; however, prospective data on testosterone, sex hormone-binding globulin (SHBG) and insulin-like growth factor (IGF)-1 are limited. To elucidate the role of these hormones in endometrial cancer risk we conducted complementary observational and Mendelian randomization (MR) analyses. METHODS: The observational analyses included 159,702 women (80% postmenopausal) enrolled in the UK Biobank. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. For MR analyses, genetic variants associated with hormone levels were identified and their association with endometrial cancer (12,906 cases/108,979 controls) was examined using two-sample MR. RESULTS: In the observational analysis, higher circulating concentrations of total (HR per unit inverse normal scale = 1.38, 95% CI = 1.22-1.57) and free testosterone (HR per unit log scale = 2.07, 95% CI = 1.66-2.58) were associated with higher endometrial cancer risk. An inverse association was found for SHBG (HR per unit inverse normal scale = 0.76, 95% CI = 0.67-0.86). Results for testosterone and SHBG were supported by the MR analyses. No association was found between genetically predicted IGF-1 concentration and endometrial cancer risk. CONCLUSIONS: Our results support probable causal associations between circulating concentrations of testosterone and SHBG with endometrial cancer risk.


Assuntos
Neoplasias do Endométrio/genética , Fator de Crescimento Insulin-Like I/metabolismo , Pós-Menopausa/sangue , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona/sangue , Idoso , Bancos de Espécimes Biológicos , Neoplasias do Endométrio/sangue , Feminino , Estudos de Associação Genética , Variação Genética , Humanos , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fatores de Risco , Reino Unido
16.
Cancers (Basel) ; 13(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206031

RESUMO

We investigated associations between serum levels of bilirubin, an endogenous antioxidant, and gastrointestinal cancer risk. In the UK Biobank, prediagnostic serum levels of total bilirubin were measured in blood samples collected from 440,948 participants. In multivariable-adjusted Cox proportional hazard regression, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for associations between bilirubin levels and gastrointestinal cancer risk (colorectum, esophagus, stomach, mouth, pancreas, and liver). After a median follow-up of 7.1 years (interquartile range: 1.4), 5033 incident gastrointestinal cancer cases were recorded. In multivariable-adjusted models, bilirubin levels were negatively associated with risk of esophageal adenocarcinoma (EAC, HR per 1-SD increment in log-total bilirubin levels 0.72, 95%CI 0.56-0.92, p = 0.01). Weak and less robust negative associations were observed for colorectal cancer (CRC, HR per 1-SD increment in log-total bilirubin levels 0.95, 95%CI 0.88-1.02, p = 0.14). Bilirubin levels were positively associated with risk of hepatocellular carcinoma (HCC, HR per 1-SD increment in log-total bilirubin levels 2.07, 95%CI 1.15-3.73, p = 0.02) and intrahepatic bile duct (IBD) cancer (HR per 1-SD increment 1.67, 95%CI 1.07-2.62, p = 0.03). We found no associations with risks of stomach, oral, and pancreatic cancers. Prediagnostic serum levels of bilirubin were negatively associated with risk of EAC and positively associated with HCC and IBD cancer. Further studies are warranted to replicate our findings for specific GI cancers.

17.
Int J Cancer ; 149(9): 1659-1669, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34196970

RESUMO

Dysregulation of tryptophan metabolism has been linked to colorectal tumorigenesis; however, epidemiological studies investigating tryptophan metabolites in relation to colorectal cancer risk are limited. We studied associations of plasma tryptophan, serotonin and kynurenine with colon cancer risk in two studies with cancer patients and controls, and in one prospective cohort: ColoCare Study (110 patients/153 controls), the Colorectal Cancer Study of Austria (CORSA; 46 patients/390 controls) and the European Prospective Investigation into Cancer and Nutrition (EPIC; 456 matched case-control pairs). Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for colon cancer risk. Tryptophan was inversely associated with colon cancer risk in ColoCare (OR per 1-SD = 0.44; 95% CI, 0.31-0.64) and EPIC (OR per 1-SD = 0.86; 95% CI, 0.74-0.99). Comparing detectable vs nondetectable levels, serotonin was positively associated with colon cancer in CORSA (OR = 6.39; 95% CI, 3.61-11.3) and EPIC (OR = 2.03; 95% CI, 1.20-3.40). Kynurenine was inversely associated with colon cancer in ColoCare (OR per 1-SD = 0.74; 95% CI, 0.55-0.98), positively associated in CORSA (OR per 1-SD = 1.79; 95% CI, 1.27-2.52), while no association was observed in EPIC. The kynurenine-to-tryptophan ratio was positively associated with colon cancer in ColoCare (OR per 1-SD = 1.38; 95% CI, 1.03-1.84) and CORSA (OR per 1-SD = 1.44; 95% CI, 1.06-1.96), but not in EPIC. These results suggest that higher plasma tryptophan may be associated with lower colon cancer risk, while increased serotonin may be associated with a higher risk of colon cancer. The kynurenine-to-tryptophan ratio may also reflect altered tryptophan catabolism during colon cancer development.


Assuntos
Neoplasias do Colo/sangue , Cinurenina/sangue , Serotonina/sangue , Triptofano/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/metabolismo , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Triptofano/metabolismo
18.
Int J Epidemiol ; 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34259837

RESUMO

BACKGROUND: Findings and limitations of previous studies on persistent organic pollutants (POPs) and pancreatic cancer risk support conducting further research in prospective cohorts. METHODS: We conducted a prospective case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Participants were 513 pancreatic cancer cases and 1020 matched controls. Concentrations of 22 POPs were measured in plasma collected at baseline. RESULTS: Some associations were observed at higher concentrations of p, p'-DDT, trans-nonachlor, ß-hexachlorocyclohexane and the sum of six organochlorine pesticides and of 16 POPs. The odds ratio (OR) for the upper quartile of trans-nonachlor was 1.55 (95% confidence interval 1.06-2.26; P for trend = 0.025). Associations were stronger in the groups predefined as most valid (participants having fasted >6 h, with microscopic diagnostic confirmation, normal weight, and never smokers), and as most relevant (follow-up ≥10 years). Among participants having fasted >6 h, the ORs were relevant for 10 of 11 exposures. Higher ORs were also observed among cases with microscopic confirmation than in cases with a clinical diagnosis, and among normal-weight participants than in the rest of participants. Among participants with a follow-up ≥10 years, estimates were higher than in participants with a shorter follow-up (for trans-nonachlor: OR = 2.14, 1.01 to 4.53, P for trend = 0.035). Overall, trans-nonachlor, three PCBs and the two sums of POPs were the exposures most clearly associated with pancreatic cancer risk. CONCLUSIONS: Individually or in combination, most of the 22 POPs analysed did not or only moderately increased the risk of pancreatic cancer.

19.
Geophys Res Lett ; 48(8): e2021GL092980, 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-34219841

RESUMO

We present the first investigation and quantification of the photoionization loss process to Mercury's sodium exosphere from spacecraft and ground-based observations. We analyze plasma and neutral sodium measurements from NASA's MESSENGER spacecraft and the THEMIS telescope. We find that the sodium ion (Na+) content and therefore the significance of photoionization varies with Mercury's orbit around the Sun (i.e., true anomaly angle: TAA). Na+ production is affected by the neutral sodium solar-radiation acceleration loss process. More Na+ was measured on the inbound leg of Mercury's orbit at 180°-360° TAA because less neutral sodium is lost downtail from radiation acceleration. Calculations using results from observations show that the photoionization loss process removes ∼1024 atoms/s from the sodium exosphere (maxima of 4 × 1024 atoms/s), showing that modeling efforts underestimate this loss process. This is an important result as it shows that photoionization is a significant loss process and larger than loss from radiation acceleration.

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