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1.
Cancer Res ; 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33820799

RESUMO

The average age at menarche declined in European and U.S. populations during the 19th and 20th centuries. The timing of pubertal events may have broad implications for chronic disease risks in aging women. Here we tested for associations of recalled menarcheal age with risks of 19 cancers in 536,450 women [median age, 60 years (range, 31-39 years)] in nine prospective U.S. and European cohorts that enrolled participants from 1981 to 1998. Cox regression estimated multivariable-adjusted HRs and 95% confidence intervals (CI) for associations of the age at menarche with risk of each cancer in each cohort and random-effects meta-analysis was used to generate summary estimates for each cancer. Over a median 10 years of follow-up, 60,968 women were diagnosed with a first primary incident cancer. Inverse linear associations were observed for seven of 19 cancers studied. Each additional year in the age at menarche was associated with reduced risks of endometrial cancer (HR = 0.91; 95% CI, 0.89-0.94), liver cancer (HR = 0.92; 95% CI, 0.85-0.99), melanoma (HR = 0.95; 95% CI, 0.93-0.98), bladder cancer (HR = 0.96; 95% CI, 0.93-0.99), and cancers of the colon (HR = 0.97; 95% CI, 0.96-0.99), lung (HR = 0.98; 95% CI, 0.96-0.99), and breast (HR = 0.98; 95% CI, 0.93-0.99). All but one of these associations remained statistically significant following adjustment for baseline body mass index. Similarities in the observed associations between menarche and seven cancers suggest shared underlying causes rooted early in life. We propose as a testable hypothesis that early exposure to sex hormones increases mid-life cancer risks by altering functional capacities of stem cells with roles in systemic energy balance and tissue homeostasis. SIGNIFICANCE: Age at menarche is associated with risk for seven cancers in middle-aged women, and understanding the shared underlying causal pathways across these cancers may suggest new avenues for cancer prevention.

2.
J Natl Cancer Inst ; 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33769540

RESUMO

BACKGROUND: Polygenic risk scores (PRS) have been demonstrated to identify women of European, Asian and Latino ancestry at elevated risk of developing breast cancer (BC). We evaluated the performance of existing PRSs trained in European ancestry populations among women of African ancestry. METHODS: We assembled genotype data for women of African ancestry, including 9,241 cases and 10,193 controls. We evaluated associations of 179- and 313-variant PRSs with overall and subtype-specific BC risk. PRS discriminatory accuracy was assessed using area under the receiver operating characteristic curve (AUC). We also evaluated a recalibrated PRS, replacing the index variant with variants in each region that better captured risk in women of African ancestry, and estimated lifetime absolute risk of BC in African Americans by PRS category. RESULTS: For overall BC, the odds ratios per standard deviation of PRS313 was 1.27 (95%CI = 1.23 to 1.31), with an AUC of 0.571 (95%CI = 0.562 to 0.579). Compared to women with average risk (40th-60th PRS percentile), women in the top decile of PRS313 had a 1.54-fold increased risk (95% CI = 1.38 to 1.72). By age 85 years, the absolute risk of overall BC was 19.6% for African American women in the top 1% of PRS313 and 6.7% for those in the lowest 1%. The recalibrated PRS did not improve BC risk prediction. CONCLUSION: The PRSs stratify BC risk in women of African ancestry, with attenuated performance compared to that reported in European, Asian and Latina populations. Future work is needed to improve BC risk stratification for women of African ancestry.

3.
Eur J Epidemiol ; 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33128203

RESUMO

Associations between anthropometric factors and breast cancer (BC) risk have varied inconsistently by estrogen and/or progesterone receptor (ER/PR) status. Associations between prediagnostic anthropometric factors and risk of premenopausal and postmenopausal BC overall and ER/PR status subtypes were investigated in a pooled analysis of 20 prospective cohorts, including 36,297 BC cases among 1,061,915 women, using multivariable Cox regression analyses, controlling for reproductive factors, diet and other risk factors. We estimated dose-response relationships and tested for nonlinear associations using restricted cubic splines. Height showed positive, linear associations for premenopausal and postmenopausal BC risk (6-7% RR increase per 5 cm increment), with stronger associations for receptor-positive subtypes. Body mass index (BMI) at cohort baseline was strongly inversely associated with premenopausal BC risk, and strongly positively-and nonlinearly-associated with postmenopausal BC (especially among women who never used hormone replacement therapy). This was primarily observed for receptor-positive subtypes. Early adult BMI (at 18-20 years) showed inverse, linear associations for premenopausal and postmenopausal BC risk (21% and 11% RR decrease per 5 kg/m2, respectively) with stronger associations for receptor-negative subtypes. Adult weight gain since 18-20 years was positively associated with postmenopausal BC risk, stronger for receptor-positive subtypes, and among women who were leaner in early adulthood. Women heavier in early adulthood generally had reduced premenopausal BC risk, independent of later weight gain. Positive associations between height, baseline (adult) BMI, adult weight gain and postmenopausal BC risk were substantially stronger for hormone receptor-positive versus negative subtypes. Premenopausal BC risk was positively associated with height, but inversely with baseline BMI and weight gain (mostly in receptor-positive subtypes). Inverse associations with early adult BMI seemed stronger in receptor-negative subtypes of premenopausal and postmenopausal BC.

4.
Blood Adv ; 4(1): 181-190, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31935283

RESUMO

Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P < 1 × 10-6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P < .05 in AA individuals. In 8 regions, we identified markers that better capture MM risk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10-12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.

5.
Int J Cancer ; 146(9): 2394-2405, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276202

RESUMO

Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all ptrend < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Biomarcadores Tumorais/sangue , Carcinoma de Células Grandes/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Inflamação/complicações , Neoplasias Pulmonares/diagnóstico , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/etiologia , Adulto , Idoso , Carcinoma de Células Grandes/sangue , Carcinoma de Células Grandes/etiologia , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/etiologia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Inflamação/sangue , Inflamação/imunologia , Cinurenina/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Neopterina/sangue , Prognóstico , Estudos Prospectivos , Fatores de Risco , Carcinoma de Pequenas Células do Pulmão/sangue , Carcinoma de Pequenas Células do Pulmão/etiologia , Triptofano/sangue
6.
Biostatistics ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31750898

RESUMO

Pooling biomarker data across multiple studies allows for examination of a wider exposure range than generally possible in individual studies, evaluation of population subgroups and disease subtypes with more statistical power, and more precise estimation of biomarker-disease associations. However, circulating biomarker measurements often require calibration to a single reference assay prior to pooling due to assay and laboratory variability across studies. We propose several methods for calibrating and combining biomarker data from nested case-control studies when reference assay data are obtained from a subset of controls in each contributing study. Specifically, we describe a two-stage calibration method and two aggregated calibration methods, named the internalized and full calibration methods, to evaluate the main effect of the biomarker exposure on disease risk and whether that association is modified by a potential covariate. The internalized method uses the reference laboratory measurement in the analysis when available and otherwise uses the estimated value derived from calibration models. The full calibration method uses calibrated biomarker measurements for all subjects, including those with reference laboratory measurements. Under the two-stage method, investigators complete study-specific analyses in the first stage followed by meta-analysis in the second stage. Our results demonstrate that the full calibration method is the preferred aggregated approach to minimize bias in point estimates. We also observe that the two-stage and full calibration methods provide similar effect and variance estimates but that their variance estimates are slightly larger than those from the internalized approach. As an illustrative example, we apply the three methods in a pooling project of nested case-control studies to evaluate (i) the association between circulating vitamin D levels and risk of stroke and (ii) how body mass index modifies the association between circulating vitamin D levels and risk of cardiovascular disease.

7.
Stat Med ; 38(8): 1303-1320, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30569596

RESUMO

Pooling data from multiple studies improves estimation of exposure-disease associations through increased sample size. However, biomarker exposure measurements can vary substantially across laboratories and often require calibration to a reference assay prior to pooling. We develop two statistical methods for aggregating biomarker data from multiple studies: the full calibration method and the internalized method. The full calibration method calibrates all biomarker measurements regardless of the availability of reference laboratory measurements while the internalized method calibrates only non-reference laboratory measurements. We compare the performance of these two aggregation methods to two-stage methods. Furthermore, we compare the aggregated and two-stage methods when estimating the calibration curve from controls only or from a random sample of individuals from the study cohort. Our findings include the following: (1) Under random sampling for calibration, exposure effect estimates from the internalized method have a smaller mean squared error than those from the full calibration method. (2) Under the controls-only calibration design, the full calibration method yields effect estimates with the least bias. (3) The two-stage approaches produce average effect estimates that are similar to the full calibration method under a controls only calibration design and the internalized method under a random sample calibration design. We illustrate the methods in an application evaluating the relationship between circulating vitamin D levels and stroke risk in a pooling project of cohort studies.


Assuntos
Biomarcadores , Calibragem , Interpretação Estatística de Dados , Projetos de Pesquisa , Algoritmos , Humanos , Razão de Chances , Projetos de Pesquisa/estatística & dados numéricos
8.
Cancer Epidemiol Biomarkers Prev ; 27(12): 1480-1482, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30108098

RESUMO

BACKGROUND: Lowering endogenous estrogen levels is one mechanism whereby physical activity may lower postmenopausal breast cancer risk. Several prospective studies have suggested that increased 2-hydroxylation of estrogens may also reduce postmenopausal breast cancer risk, but whether or not exercise alters estrogen metabolism through this mechanism is unclear. METHODS: We measured total circulating concentrations of parent estrogens (estrone and estradiol) and 13 estrogen metabolites, including glucuronidated, sulfated, and unconjugated forms, by stable isotope dilution LC/MS-MS in 153 postmenopausal women randomized to 12 months of moderate-to-vigorous exercise and 153 controls. We also explored associations with cardiorespiratory fitness measured by treadmill. RESULTS: Although women randomized to exercise averaged 178 minutes/week of exercise over 12 months, their cardiorespiratory fitness was 13% greater than controls at 12 months (P = 0.0001), and total estradiol was reduced by 10% (P = 0.04); there were no statistically significant effects of exercise on circulating concentrations of estrogen metabolites in the 2-, 4-, or 16-pathways, or on the 2-pathway/parent estrogens ratio. However, we observed a statistically significant association between increased fitness and reduced concentration of 2-pathway metabolites (P < 0.05). CONCLUSIONS: We found no evidence that 12 months of moderate-to-vigorous exercise or increased fitness changed estrogen metabolism in a way that might reduce breast cancer risk. IMPACT: The protective effect of exercise on postmenopausal breast cancer is unlikely to be mediated by changes in estrogen metabolism.


Assuntos
Aptidão Cardiorrespiratória/fisiologia , Estrogênios/metabolismo , Exercício Físico/fisiologia , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Fatores de Risco
9.
Cancer Epidemiol Biomarkers Prev ; 27(5): 585-593, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29511040

RESUMO

Background: Estrogen metabolism in premenopausal women may be related to early life body fatness.Methods: Premenopausal women participating in the Nurses' Health Study II recalled their body fatness at ages 5, 10, and 20 years using a validated 9-level pictogram. Fifteen estrogens and estrogen metabolites (EM) were measured using LC/MS-MS in luteal phase urines from 603 women ages 32-54 years. Geometric means of individual EM, metabolic pathway groups, and pathway ratios were examined by body fatness categories using linear mixed models.Results: Body fatness at each age was inversely associated with adult concentrations of all EM combined, parent estrogens (estrone, estradiol), and the 2-hydroxylation pathway. Women in the top (vs. bottom) category of body fatness at age 10 had 21% lower levels of all EM (Ptrend = 0.003), 24% lower parent estrogens (Ptrend = 0.002), and 36% lower 2-pathway (Ptrend = 0.0003). Body fatness at age 10 was inversely associated with 2-catechols (35% lower, Ptrend = 0.0004) and 2-methylated catechols (30% lower, Ptrend = 0.002). After adjusting for premenopausal body mass index (BMI), these associations remained inverse but were attenuated; only parent estrogens remained statistically significant (21% lower, Ptrend = 0.01). Body fatness at ages 5 and 20 were similarly, but more weakly, associated with estrogen pathways.Conclusions: Estimates of body fatness during early life were inversely associated with premenopausal levels of all EM combined, parent estrogens, and 2-pathway estrogen metabolites. These relationships were not fully explained by adult BMI.Impact: These findings inform investigations of diseases linked to early life body fatness and estrogen metabolism. Cancer Epidemiol Biomarkers Prev; 27(5); 585-93. ©2018 AACR.


Assuntos
Adiposidade/fisiologia , Neoplasias da Mama/prevenção & controle , Estrogênios/urina , Pré-Menopausa/metabolismo , Adolescente , Adulto , Índice de Massa Corporal , Neoplasias da Mama/metabolismo , Criança , Cromatografia Líquida de Alta Pressão/métodos , Estrogênios/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Pré-Menopausa/urina , Estudos Prospectivos , Fatores de Risco , Espectrometria de Massas em Tandem/métodos , Adulto Jovem
10.
J Natl Cancer Inst ; 110(6): 588-597, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29325144

RESUMO

Background: Elevated body mass index (BMI) is associated with increased risk of postmenopausal breast cancer. The underlying mechanisms, however, remain elusive. Methods: In a nested case-control study of 621 postmenopausal breast cancer case participants and 621 matched control participants, we measured 617 metabolites in prediagnostic serum. We calculated partial Pearson correlations between metabolites and BMI, and then evaluated BMI-associated metabolites (Bonferroni-corrected α level for 617 statistical tests = P < 8.10 × 10-5) in relation to invasive breast cancer. Odds ratios (ORs) of breast cancer comparing the 90th vs 10th percentile (modeled on a continuous basis) were estimated using conditional logistic regression while controlling for breast cancer risk factors, including BMI. Metabolites with the lowest P values (false discovery rate < 0.2) were mutually adjusted for one another to determine those independently associated with breast cancer risk. Results: Of 67 BMI-associated metabolites, two were independently associated with invasive breast cancer risk: 16a-hydroxy-DHEA-3-sulfate (OR = 1.65, 95% confidence interval [CI] = 1.22 to 2.22) and 3-methylglutarylcarnitine (OR = 1.67, 95% CI = 1.21 to 2.30). Four metabolites were independently associated with estrogen receptor-positive (ER+) breast cancer risk: 16a-hydroxy-DHEA-3-sulfate (OR = 1.84, 95% CI = 1.27 to 2.67), 3-methylglutarylcarnitine (OR = 1.91, 95% CI = 1.23 to 2.96), allo-isoleucine (OR = 1.76, 95% CI = 1.23 to 2.51), and 2-methylbutyrylcarnitine (OR = 1.89, 95% CI = 1.22 to 2.91). In a model without metabolites, each 5 kg/m2 increase in BMI was associated with a 14% higher risk of breast cancer (OR = 1.14, 95% CI = 1.01 to 1.28), but adding 16a-hydroxy-DHEA-3-sulfate and 3-methylglutarylcarnitine weakened this association (OR = 1.06, 95% CI = 0.93 to 1.20), with the logOR attenuating by 57.6% (95% CI = 21.8% to 100.0+%). Conclusion: These four metabolites may signal metabolic pathways that contribute to breast carcinogenesis and that underlie the association of BMI with increased postmenopausal breast cancer risk. These findings warrant further replication efforts.


Assuntos
Índice de Massa Corporal , Neoplasias da Mama/etiologia , Neoplasias da Mama/metabolismo , Metaboloma , Pós-Menopausa/metabolismo , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Detecção Precoce de Câncer/métodos , Feminino , Humanos , Programas de Rastreamento/métodos , Metabolômica/métodos , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Estados Unidos/epidemiologia
11.
J Natl Cancer Inst ; 110(1)2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28922778

RESUMO

Background: Circulating concentrations of B vitamins and factors related to one-carbon metabolism have been found to be strongly inversely associated with lung cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The extent to which these associations are present in other study populations is unknown. Methods: Within 20 prospective cohorts from the National Cancer Institute Cohort Consortium, a nested case-control study was designed including 5364 incident lung cancer case patients and 5364 control subjects who were individually matched to case patients by age, sex, cohort, and smoking status. Centralized biochemical analyses were performed to measure circulating concentrations of vitamin B6, folate, and methionine, as well as cotinine as an indicator of recent tobacco exposure. The association between these biomarkers and lung cancer risk was evaluated using conditional logistic regression models. Results: Participants with higher circulating concentrations of vitamin B6 and folate had a modestly decreased risk of lung cancer risk overall, the odds ratios when comparing the top and bottom fourths (OR 4vs1 ) being 0.88 (95% confidence interval [CI] = 0.78 to 1.00) and 0.86 (95% CI = 0.74 to 0.99), respectively. We found stronger associations among men (vitamin B6: OR 4vs1 = 0.74, 95% CI = 0.62 to 0.89; folate: OR 4vs1 = 0.75, 95% CI = 0.61 to 0.93) and ever smokers (vitamin B6: OR 4vs1 = 0.78, 95% CI = 0.67 to 0.91; folate: OR 4vs1 = 0.87, 95% CI = 0.73 to 1.03). We further noted that the association of folate was restricted to Europe/Australia and Asia, whereas no clear association was observed for the United States. Circulating concentrations of methionine were not associated with lung cancer risk overall or in important subgroups. Conclusions: Although confounding by tobacco exposure or reverse causation cannot be ruled out, these study results are compatible with a small decrease in lung cancer risk in ever smokers who avoid low concentrations of circulating folate and vitamin B6.


Assuntos
Ácido Fólico/sangue , Neoplasias Pulmonares/epidemiologia , Metionina/sangue , Vitamina B 6/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Ásia/epidemiologia , Austrália/epidemiologia , Estudos de Casos e Controles , Cotinina/sangue , Europa (Continente)/epidemiologia , Feminino , Humanos , Incidência , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Proteção , Fatores de Risco , Fatores Sexuais , Fumar/sangue , Fumar/epidemiologia , Estados Unidos/epidemiologia
12.
Int J Cancer ; 142(6): 1182-1188, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29114882

RESUMO

We assessed the association between 1,414 single nucleotide polymorphisms (SNPs) in genes involved in synthesis and metabolism of steroid hormones and insulin-like growth factor 1, and risk of breast cancer in situ (BCIS), with the aim of determining whether any of these were disease specific. This was carried out using 1,062 BCIS cases and 10,126 controls as well as 6,113 invasive breast cancer cases from the Breast and Prostate Cancer Cohort Consortium (BPC3). Three SNPs showed at least one nominally significant association in homozygous minor versus homozygous major models. ACVR2A-rs2382112 (ORhom = 3.05, 95%CI = 1.72-5.44, Phom = 1.47 × 10-4 ), MAST2-rs12124649 (ORhom = 1.73, 95% CI =1.18-2.54, Phom = 5.24 × 10-3 ), and INSR-rs10500204 (ORhom = 1.96, 95% CI = 1.44-2.67, Phom =1.68 × 10-5 ) were associated with increased risk of BCIS; however, only the latter association was significant after correcting for multiple testing. Furthermore, INSR-rs10500204 was more strongly associated with the risk of BCIS than invasive disease in case-only analyses using the homozygous minor versus homozygous major model (ORhom = 1.78, 95% CI = 1.30-2.44, Phom = 3.23 × 10-4 ). The SNP INSR-rs10500204 is located in an intron of the INSR gene and is likely to affect binding of the promyelocytic leukemia (PML) protein. The PML gene is known as a tumor suppressor and growth regulator in cancer. However, it is not clear on what pathway the A-allele of rs10500204 could operate to influence the binding of the protein. Hence, functional studies are warranted to investigate this further.


Assuntos
Receptores de Activinas Tipo II/genética , Antígenos CD/genética , Carcinoma de Mama in situ/genética , Neoplasias da Mama/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Serina-Treonina Quinases/genética , Receptor de Insulina/genética , Receptores de Activinas Tipo II/metabolismo , Idoso , Antígenos CD/metabolismo , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença/genética , Hormônios Esteroides Gonadais/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Íntrons/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Proteína da Leucemia Promielocítica/metabolismo , Estudos Prospectivos , Proteínas Serina-Treonina Quinases/metabolismo , Receptor de Insulina/metabolismo
13.
Int J Cancer ; 142(12): 2425-2434, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29238985

RESUMO

Circulating vitamin B6 levels have been found to be inversely associated with lung cancer. Most studies have focused on the B6 form pyridoxal 5'-phosphate (PLP), a direct biomarker influenced by inflammation and other factors. Using a functional B6 marker allows further investigation of the potential role of vitamin B6 status in the pathogenesis of lung cancer. We prospectively evaluated the association of the functional marker of vitamin B6 status, the 3-hydroxykynurenine:xanthurenic acid (HK:XA) ratio, with risk of lung cancer in a nested case-control study consisting of 5,364 matched case-control pairs from the Lung Cancer Cohort Consortium (LC3). We used conditional logistic regression to evaluate the association between HK:XA and lung cancer, and random effect models to combine results from different cohorts and regions. High levels of HK:XA, indicating impaired functional B6 status, were associated with an increased risk of lung cancer, the odds ratio comparing the fourth and the first quartiles (OR4thvs.1st ) was 1.25 (95% confidence interval, 1.10-1.41). Stratified analyses indicated that this association was primarily driven by cases diagnosed with squamous cell carcinoma. Notably, the risk associated with HK:XA was approximately 50% higher in groups with a high relative frequency of squamous cell carcinoma, i.e., men, former and current smokers. This risk of squamous cell carcinoma was present in both men and women regardless of smoking status.


Assuntos
Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/patologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Vitamina B 6/sangue , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco
14.
Breast Cancer Res ; 19(1): 94, 2017 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-28821281

RESUMO

BACKGROUND: Several studies have suggested that global DNA methylation in circulating white blood cells (WBC) is associated with breast cancer risk. METHODS: To address conflicting results and concerns that the findings for WBC DNA methylation in some prior studies may reflect disease effects, we evaluated the relationship between global levels of WBC DNA methylation in white blood cells and breast cancer risk in a case-control study nested within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) cohort. A total of 428 invasive breast cancer cases and 419 controls, frequency matched on age at entry (55-59, 60-64, 65-69, ≥70 years), year of entry (on/before September 30, 1997, on/after October 1, 1997) and period of DNA extraction (previously extracted, newly extracted) were included. The ratio of 5-methyl-2' deoxycytidine [5-mdC] to 2'-deoxyguanine [dG], assuming [dG] = [5-mdC] + [2'-deoxycytidine [dC]] (%5-mdC), was determined by liquid chromatography-electrospray ionization-tandem mass spectrometry, an especially accurate method for assessing total genomic DNA methylation. RESULTS: Odds ratio (OR) estimates and 95% confidence intervals (CI) for breast cancer risk adjusted for age at entry, year of entry, and period of DNA extraction, were 1.0 (referent), 0.89 (95% CI, 0.6-1.3), 0.88 (95% CI, 0.6-1.3), and 0.84 (95% CI, 0.6-1.2) for women in the highest compared to lowest quartile levels of %5md-C (p for trend = .39). Effects did not meaningfully vary by time elapsed from WBC collection to diagnosis. DISCUSSION: These results do not support the hypothesis that global DNA hypomethylation in WBC DNA is associated with increased breast cancer risk prior to the appearance of clinical disease.


Assuntos
Neoplasias da Mama Masculina/epidemiologia , Neoplasias da Mama/epidemiologia , Metilação de DNA/genética , Leucócitos , Células Neoplásicas Circulantes , Biomarcadores Tumorais/sangue , Neoplasias da Mama/etiologia , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/etiologia , Neoplasias da Mama Masculina/patologia , Ensaios Clínicos como Assunto , Neoplasias Colorretais/sangue , Neoplasias Colorretais/complicações , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Masculino , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Neoplasias da Próstata/sangue , Neoplasias da Próstata/complicações , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Fatores de Risco
15.
Am J Clin Nutr ; 106(2): 637-649, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28659298

RESUMO

Background: The epidemiologic evidence for associations between dietary factors and breast cancer is weak and etiologic mechanisms are often unclear. Exploring the role of dietary biomarkers with metabolomics can potentially facilitate objective dietary characterization, mitigate errors related to self-reported diet, agnostically test metabolic pathways, and identify mechanistic mediators.Objective: The aim of this study was to evaluate associations of diet-related metabolites with the risk of breast cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.Design: We examined prediagnostic serum concentrations of diet-related metabolites in a nested case-control study in 621 postmenopausal invasive breast cancer cases and 621 matched controls in the multicenter PLCO cohort. We calculated partial Pearson correlations between 617 metabolites and 55 foods, food groups, and vitamin supplements on the basis of the 2015 Dietary Guidelines for Americans and derived from a 137-item self-administered food-frequency questionnaire. Diet-related metabolites (P-correlation < 1.47 × 10-6) were evaluated in breast cancer analyses. ORs for the 90th compared with the 10th percentile were calculated by using conditional logistic regression, with body mass index, physical inactivity, other breast cancer risk factors, and caloric intake controlled for (false discovery rate <0.2).Results: Of 113 diet-related metabolites, 3 were associated with overall breast cancer risk (621 cases): caprate (10:0), a saturated fatty acid (OR: 1.77; 95% CI = 1.28, 2.43); γ-carboxyethyl hydrochroman (γ-CEHC), a vitamin E (γ-tocopherol) derivative (OR: 1.64; 95% CI: 1.18, 2.28); and 4-androsten-3ß,17ß-diol-monosulfate (1), an androgen (OR: 1.61; 95% CI: 1.20, 2.16). Nineteen metabolites were significantly associated with estrogen receptor (ER)-positive (ER+) breast cancer (418 cases): 12 alcohol-associated metabolites, including 7 androgens and α-hydroxyisovalerate (OR: 2.23; 95% CI: 1.50, 3.32); 3 vitamin E (tocopherol) derivatives (e.g., γ-CEHC; OR: 1.80; 95% CI: 1.20, 2.70); butter-associated caprate (10:0) (OR: 1.81; 95% CI: 1.23, 2.67); and fried food-associated 2-hydroxyoctanoate (OR: 1.46; 95% CI: 1.03, 2.07). No metabolites were significantly associated with ER-negative breast cancer (144 cases).Conclusions: Prediagnostic serum concentrations of metabolites related to alcohol, vitamin E, and animal fats were moderately strongly associated with ER+ breast cancer risk. Our findings show how nutritional metabolomics might identify diet-related exposures that modulate cancer risk. This trial was registered at clinicaltrials.gov as NCT00339495.


Assuntos
Neoplasias da Mama/sangue , Dieta , Gorduras na Dieta/sangue , Etanol/sangue , Ácidos Graxos/sangue , Comportamento Alimentar , Tocoferóis/sangue , Idoso , Androgênios/sangue , Animais , Biomarcadores/sangue , Neoplasias da Mama/etiologia , Manteiga , Estudos de Casos e Controles , Ácidos Decanoicos/sangue , Gorduras na Dieta/efeitos adversos , Suplementos Nutricionais , Etanol/efeitos adversos , Ácidos Graxos/efeitos adversos , Feminino , Humanos , Modelos Logísticos , Metabolômica , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores Estrogênicos/metabolismo , Fatores de Risco , Tocoferóis/efeitos adversos
16.
NPJ Breast Cancer ; 3: 5, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28649645

RESUMO

A coding region polymorphism exists in the TP53 gene (Pro47Ser; rs1800371) in individuals of African descent, which reduces p53 tumor suppressor function in a mouse model. It has been unclear whether this functionally significant polymorphism alters cancer risk in humans. This analysis included 6907 women with breast cancer and 7644 controls from the AMBER, ROOT, and AABC consortia. We used multivariable logistic regression to estimate associations between the TP53 Pro47Ser allele and overall breast cancer risk. Because polymorphisms in TP53 tend to be associated with cancer risk in pre-menopausal women, we also limited our analyses to this population in the AMBER and ROOT consortia, where menopausal status was known, and conducted a fixed effects meta-analysis. In an analysis of all women in the AMBER, ROOT, and AABC consortia, we found no evidence for association of the Pro47Ser variant with breast cancer risk. However, when we restricted our analysis to only pre-menopausal women from the AMBER and ROOT consortia, there was a per allele odds ratio of 1.72 (95% confidence interval 1.08-2.76; p-value = 0.023). Although the Pro47Ser variant was not associated with overall breast cancer risk, it may increase risk among pre-menopausal women of African ancestry. Following up on more studies in human populations may better elucidate the role of this variant in breast cancer etiology. However, because of the low frequency of the polymorphism in women of African ancestry, its impact at a population level may be minimal.

17.
Cancer Epidemiol Biomarkers Prev ; 26(7): 1016-1026, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28377418

RESUMO

Background: Genome-wide association studies have identified approximately 100 common genetic variants associated with breast cancer risk, the majority of which were discovered in women of European ancestry. Because of different patterns of linkage disequilibrium, many of these genetic markers may not represent signals in populations of African ancestry.Methods: We tested 74 breast cancer risk variants and conducted fine-mapping of these susceptibility regions in 6,522 breast cancer cases and 7,643 controls of African ancestry from three genetic consortia (AABC, AMBER, and ROOT).Results: Fifty-four of the 74 variants (73%) were found to have ORs that were directionally consistent with those previously reported, of which 12 were nominally statistically significant (P < 0.05). Through fine-mapping, in six regions (3p24, 12p11, 14q13, 16q12/FTO, 16q23, 19p13), we observed seven markers that better represent the underlying risk variant for overall breast cancer or breast cancer subtypes, whereas in another two regions (11q13, 16q12/TOX3), we identified suggestive evidence of signals that are independent of the reported index variant. Overlapping chromatin features and regulatory elements suggest that many of the risk alleles lie in regions with biological functionality.Conclusions: Through fine-mapping of known susceptibility regions, we have revealed alleles that better characterize breast cancer risk in women of African ancestry.Impact: The risk alleles identified represent genetic markers for modeling and stratifying breast cancer risk in women of African ancestry. Cancer Epidemiol Biomarkers Prev; 26(7); 1016-26. ©2017 AACR.


Assuntos
Afro-Americanos/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Alelos , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Mapeamento Cromossômico , Feminino , Loci Gênicos , Humanos , Polimorfismo de Nucleotídeo Único , Receptores Estrogênicos/metabolismo , Fatores de Risco
18.
Cancer Epidemiol Biomarkers Prev ; 26(8): 1276-1287, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28446545

RESUMO

Background: Relationships between fruit, vegetable, and mature bean consumption and prostate cancer risk are unclear.Methods: We examined associations between fruit and vegetable groups, specific fruits and vegetables, and mature bean consumption and prostate cancer risk overall, by stage and grade, and for prostate cancer mortality in a pooled analysis of 15 prospective cohorts, including 52,680 total cases and 3,205 prostate cancer-related deaths among 842,149 men. Diet was measured by a food frequency questionnaire or similar instrument at baseline. We calculated study-specific relative risks using Cox proportional hazards regression, and then pooled these estimates using a random effects model.Results: We did not observe any statistically significant associations for advanced prostate cancer or prostate cancer mortality with any food group (including total fruits and vegetables, total fruits, total vegetables, fruit and vegetable juice, cruciferous vegetables, and tomato products), nor specific fruit and vegetables. In addition, we observed few statistically significant results for other prostate cancer outcomes. Pooled multivariable relative risks comparing the highest versus lowest quantiles across all fruit and vegetable exposures and prostate cancer outcomes ranged from 0.89 to 1.09. There was no evidence of effect modification for any association by age or body mass index.Conclusions: Results from this large, international, pooled analysis do not support a strong role of collective groupings of fruits, vegetables, or mature beans in prostate cancer.Impact: Further investigation of other dietary exposures, especially indicators of bioavailable nutrient intake or specific phytochemicals, should be considered for prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 26(8); 1276-87. ©2017 AACR.


Assuntos
Frutas/química , Phaseolus/química , Neoplasias da Próstata/prevenção & controle , Verduras/química , Estudos de Coortes , Humanos , Masculino , Estudos Prospectivos , Neoplasias da Próstata/patologia , Fatores de Risco
19.
Am J Clin Nutr ; 105(6): 1314-1326, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28424186

RESUMO

Background: Circulating concentrations of biomarkers that are related to vitamin status vary by factors such as diet, fortification, and supplement use. Published biomarker concentrations have also been influenced by the variation across laboratories, which complicates a comparison of results from different studies.Objective: We robustly and comprehensively assessed differences in biomarkers that are related to vitamin status across geographic regions.Design: The trial was a cross-sectional study in which we investigated 38 biomarkers that are related to vitamin status and one-carbon and tryptophan metabolism in serum and plasma from 5314 healthy control subjects representing 20 cohorts recruited from the United States, Nordic countries, Asia, and Australia, participating in the Lung Cancer Cohort Consortium. All samples were analyzed in a centralized laboratory.Results: Circulating concentrations of riboflavin, pyridoxal 5'-phosphate, folate, vitamin B-12, all-trans retinol, 25-hydroxyvitamin D, and α-tocopherol as well as combined vitamin scores that were based on these nutrients showed that the general B-vitamin concentration was highest in the United States and that the B vitamins and lipid soluble vitamins were low in Asians. Conversely, circulating concentrations of metabolites that are inversely related to B vitamins involved in the one-carbon and kynurenine pathways were high in Asians. The high B-vitamin concentration in the United States appears to be driven mainly by multivitamin-supplement users.Conclusions: The observed differences likely reflect the variation in intake of vitamins and, in particular, the widespread multivitamin-supplement use in the United States. The results provide valuable information about the differences in biomarker concentrations in populations across continents.


Assuntos
Carbono/sangue , Cinurenina/sangue , Vitamina A/sangue , Complexo Vitamínico B/sangue , Vitamina D/sangue , alfa-Tocoferol/sangue , Idoso , Ásia , Austrália , Biomarcadores/sangue , Estudos Transversais , Suplementos Nutricionais , Feminino , Humanos , Laboratórios , Masculino , Pessoa de Meia-Idade , Países Escandinavos e Nórdicos , Triptofano/sangue , Estados Unidos
20.
Cancer Epidemiol Biomarkers Prev ; 26(7): 1060-1070, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28264875

RESUMO

Background: Lung cancer is the leading cause of cancer death. Little is known about whether prediagnostic nutritional factors may affect survival. We examined the associations of prediagnostic calcium intake from foods and/or supplements with lung cancer survival.Methods: The present analysis included 23,882 incident, primary lung cancer patients from 12 prospective cohort studies. Dietary calcium intake was assessed using food-frequency questionnaires at baseline in each cohort and standardized to caloric intake of 2,000 kcal/d for women and 2,500 kcal/d for men. Stratified, multivariable-adjusted Cox regression was applied to compute hazard ratios (HR) and 95% confidence intervals (CI).Results: The 5-year survival rates were 56%, 21%, and 5.7% for localized, regional, and distant stage lung cancer, respectively. Low prediagnostic dietary calcium intake (<500-600 mg/d, less than half of the recommendation) was associated with a small increase in risk of death compared with recommended calcium intakes (800-1,200 mg/d); HR (95% CI) was 1.07 (1.01-1.13) after adjusting for age, stage, histology, grade, smoking status, pack-years, and other potential prognostic factors. The association between low calcium intake and higher lung cancer mortality was evident primarily among localized/regional stage patients, with HR (95% CI) of 1.15 (1.04-1.27). No association was found for supplemental calcium with survival in the multivariable-adjusted model.Conclusions: This large pooled analysis is the first, to our knowledge, to indicate that low prediagnostic dietary calcium intake may be associated with poorer survival among early-stage lung cancer patients.Impact: This multinational prospective study linked low calcium intake to lung cancer prognosis. Cancer Epidemiol Biomarkers Prev; 26(7); 1060-70. ©2017 AACR.


Assuntos
Cálcio na Dieta , Suplementos Nutricionais , Comportamento Alimentar , Neoplasias Pulmonares/mortalidade , Idoso , Inquéritos sobre Dietas/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida
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