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1.
Metabolites ; 11(2)2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33578791

RESUMO

Breast cancer is the most common cancer in women, but its incidence can only be partially explained through established risk factors. Our aim was to use metabolomics to identify novel risk factors for breast cancer and to validate recently reported metabolite-breast cancer findings. We measured levels of 1275 metabolites in prediagnostic serum in a nested case-control study of 782 postmenopausal breast cancer cases and 782 matched controls. Metabolomics analysis was performed by Metabolon Inc using ultra-performance liquid chromatography and a Q-Exactive high resolution/accurate mass spectrometer. Controls were matched by birth date, date of blood draw, and race/ethnicity. Odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer at the 90th versus 10th percentile (modeled on a continuous basis) of metabolite levels were estimated using conditional logistic regression, with adjustment for age. Twenty-four metabolites were significantly associated with breast cancer risk at a false discovery rate <0.20. For the nine metabolites positively associated with risk, the ORs ranged from 1.75 (95% CI: 1.29-2.36) to 1.45 (95% CI: 1.13-1.85), and for the 15 metabolites inversely associated with risk, ORs ranged from 0.59 (95% CI: 0.43-0.79) to 0.69 (95% CI: 0.55-0.87). These metabolites largely comprised carnitines, glycerolipids, and sex steroid metabolites. Associations for three sex steroid metabolites validated findings from recent studies and the remainder were novel. These findings contribute to growing data on metabolite-breast cancer associations by confirming prior findings and identifying novel leads for future validation efforts.

2.
Nat Genet ; 53(1): 65-75, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33398198

RESUMO

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.


Assuntos
Grupos de Populações Continentais/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias da Próstata/genética , Humanos , Masculino , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Invasividade Neoplásica , Razão de Chances , Neoplasias da Próstata/diagnóstico , Fatores de Risco
3.
J Nutr ; 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33484132

RESUMO

BACKGROUND: Valid assessment of dietary intake in diverse populations is important for studies of chronic disease risk in the United States. OBJECTIVES: We evaluated the reproducibility and validity of a food frequency questionnaire (FFQ) modified for the American Cancer Society's Cancer Prevention Study-3 (CPS-3) prospective cohort, among a racially/ethnically diverse subgroup. METHODS: The Diet Assessment Substudy included 677 CPS-3 participants (64% women; 61% non-Hispanic white, 24% non-Hispanic black, 15% Hispanic), aged 31-70 y, who completed 2 FFQs 1 y apart (FFQ1, FFQ2), 4-6 telephone-administered 24-h dietary recalls (24HRs), and 2 fasting blood samples and 24-h urine collections ∼6 mo apart in the interim. Spearman rank correlation coefficients (ρ) were used to evaluate FFQ reproducibility and validity compared with 24HRs for 67 nutrient exposures. For 18 of these nutrients, we used the method of triads to calculate validity coefficients (VCs, ρ) from pairwise correlations of FFQ2, 24HRs, and biomarkers. Analyses were stratified by sex, race/ethnicity, education, and BMI. RESULTS: Mean (range) FFQ reproducibility correlations were ρ = 0.65 (0.50-0.91) for men and ρ = 0.63 (0.37-0.89) for women; mean (range) energy-adjusted, deattenuated correlations of FFQ2 with 24HRs were ρ = 0.60 (0.33-0.84) for men and ρ = 0.55 (0.21-0.79) for women. FFQ2 VCs (ρ) among men ranged from 0.42 for ß-cryptoxanthin to 0.91 for omega-3 (n-3) fatty acids and, among women, from 0.41 for sodium to 0.79 for total vitamin D. Mean FFQ reproducibility and validity were highest among whites (ρ = 0.68, ρ = 0.58, respectively) and slightly lower among blacks (ρ = 0.57, ρ = 0.49, respectively) and Hispanics (ρ = 0.59, 0.55, respectively). FFQ reproducibility and validity were slightly lower among those with less than a 4-y college degree, and those with a BMI ≥30 kg/m2. CONCLUSIONS: Reproducibility and validity of the CPS-3 FFQ were comparable with similar studies for most nutrients, among all subgroups. These findings support future dietary analyses in the contemporary CPS-3 cohort and other similar cohorts.

5.
Front Med ; 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32889700

RESUMO

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

6.
Cancer Epidemiol Biomarkers Prev ; 29(12): 2680-2685, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32962978

RESUMO

BACKGROUND: Some evidence suggests the association between body mass index (BMI) and pancreatic cancer risk is weaker among current smokers than among never smokers. METHODS: We examined the association between BMI and pancreatic cancer mortality among adults who reported smoking status at enrollment into Cancer Prevention Study-II in 1982, including 420,543 never smokers, 282,244 former cigarette smokers, and 219,885 current cigarette smokers. After excluding the first 3 years of follow-up to reduce reverse causation, we calculated multivariable-adjusted hazard ratios (HR). RESULTS: During the full follow-up period from 1985 to 2014, 7,904 participants died of pancreatic cancer. The HR per 5 BMI units was lower among current smokers [HR = 1.14; 95% confidence interval (CI), 1.07-1.20] than never smokers (HR = 1.22; 95% CI, 1.17-1.27), although this difference was not statistically significant (P = 0.06). BMI was significantly less strongly associated with pancreatic cancer mortality among current smokers reporting ≥20 cigarettes/day (HR = 1.10; 95% CI, 1.03-1.18) than among never smokers. During follow-up within 10 years of enrollment, when current smokers at enrollment were the most likely to have still been smoking, BMI was not associated with pancreatic cancer mortality among current smokers (HR = 1.02; 95% CI, 0.90-1.16, P = 0.03 for difference between current and never smokers). BMI HRs were similar among former and never smokers. CONCLUSIONS: These results support a weaker association between BMI and pancreatic cancer among current smokers than among never smokers. IMPACT: In populations with low smoking prevalence, the pancreatic cancer burden due to BMI is likely to be higher than that predicted by risk estimates from studies including substantial numbers of smokers.

7.
Metabolites ; 10(10)2020 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-32993181

RESUMO

Previous metabolomic studies have identified putative blood biomarkers of dietary intake. These biomarkers need to be replicated in other populations and tested for reproducibility over time for the potential use in future epidemiological studies. We conducted a metabolomics analysis among 671 racially/ethnically diverse men and women included in a diet validation study to examine the correlation between >100 food groups/items (101 by a food frequency questionnaire (FFQ), 105 by 24-h diet recalls (24HRs)) with 1141 metabolites measured in fasting plasma sample replicates, six months apart. Diet-metabolite associations were examined by Pearson's partial correlation analysis. Biomarker reproducibility was assessed using intraclass correlation coefficients (ICCs). A total of 677 diet-metabolite associations were identified after Bonferroni adjustment for multiple comparisons and restricting absolute correlation coefficients to greater than 0.2 (601 associations using the FFQ and 395 using 24HRs). The median ICCs of the 238 putative biomarkers was 0.56 (interquartile range 0.46-0.68). In this study, with repeated FFQs, 24HRs and plasma metabolic profiles, we identified several potentially novel food biomarkers and replicated others found in our previous study. Our findings contribute to the growing literature on food-based biomarkers and provide important information on biomarker reproducibility which could facilitate their utilization in future nutritional epidemiological studies.

8.
J Natl Cancer Inst ; 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32853339

RESUMO

BACKGROUND: There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive versus non-aggressive disease. METHODS: Participants were 5,545 European-ancestry men, including 2,775 non-aggressive and 2,770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency<0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are two-sided. RESULTS: BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of non-aggressive cases carrying P/LP/D BRCA2 alleles (OR = 3.19, 95% CI = 1.94 to 5.25, P = 8.58x10-7) and 0.65% of aggressive and 0.11% of non-aggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79x10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of non-aggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P=.02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than non-aggressive cases (carrier frequencies=14.2% versus 10.6%, respectively; P = 5.56x10-5). However, this difference was statistically non-significant (P=.18) upon excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI=-1,65 to 0.48, P = 3.71x10-4). CONCLUSIONS: Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations.

9.
Muscle Nerve ; 62(3): 351-357, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32511765

RESUMO

INTRODUCTION: We sought to determine whether survival motor neuron (SMN) protein blood levels correlate with denervation and SMN2 copies in spinal muscular atrophy (SMA). METHODS: Using a mixed-effect model, we tested associations between SMN levels, compound muscle action potential (CMAP), and SMN2 copies in a cohort of 74 patients with SMA. We analyzed a subset of 19 of these patients plus four additional patients who had been treated with received gene therapy to examine SMN trajectories early in life. RESULTS: Patients with SMA who had lower CMAP values had lower circulating SMN levels (P = .04). Survival motor neuron protein levels were different between patients with two and three SMN2 copies (P < .0001) and between symptomatic and presymptomatic patients (P < .0001), with the highest levels after birth and progressive decline over the first 3 years. Neither nusinersen nor gene therapy clearly altered SMN levels. DISCUSSION: These data provide evidence that whole blood SMN levels correlate with SMN2 copy number and severity of denervation.


Assuntos
Potenciais de Ação/fisiologia , Músculo Esquelético/fisiopatologia , Atrofia Muscular Espinal/sangue , Proteína 1 de Sobrevivência do Neurônio Motor/sangue , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/fisiopatologia , Índice de Gravidade de Doença
10.
Int J Cancer ; 147(11): 3110-3118, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32506449

RESUMO

Cadmium and lead are persistent environmental toxins that are known or probable carcinogens, based on evidence for causality for nonhematologic cancers. Associations of these metals with risk of non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) are unknown but biologically plausible. To examine the associations of circulating levels of lead and cadmium exposure with risk of B-cell NHL (B-NHL) and multiple myeloma, we conducted a nested case-control study among 299 incident B-cell NHLs and 76 MM cases within the Cancer Prevention Study-II Nutrition Cohort (CPS-II NC). Each case was incidence-density matched to two eligible controls on age, race, sex and blood draw date. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) for lymphoid malignancies overall and stratified by subtype. We observed a significant positive association between high erythrocyte lead concentration and risk of lymphoid malignancies overall (RR = 1.16, 95% CI: 1.02-1.33 per 17.6 µg/L (1 standard deviation [SD])) and follicular lymphoma in particular (RR = 1.80, 95% CI: 1.15-2.80 per SD). In contrast, there was no association between erythrocyte cadmium and risk of B-NHL (RR = 0.89, 95% CI: 0.75-1.06 per 0.37 µg/L [1 SD]), or any B-NHL subtypes; but a strong inverse association with MM risk (RR = 0.59, 95% CI: 0.38-0.89, per SD). Results from our study suggest a positive association between erythrocyte lead level and risk of lymphoid malignancies and a possible inverse association between cadmium and myeloma. Additional research is needed to confirm and further explore these findings.

11.
Eur Urol ; 78(3): 316-320, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32409115

RESUMO

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13-7.22) and 33.41 (95% CI = 10.86-102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17-25%) for TA heterozygotes and 38% (95% CI = 13-65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. PATIENT SUMMARY: We found that rs72725854, an African ancestry-specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening.

12.
Int J Cancer ; 147(8): 2075-2090, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32285447

RESUMO

Deficient intake of micronutrients involved in one-carbon metabolism (eg, choline, methionine, vitamin B12 and folic acid) leads to hepatocellular carcinoma (HCC) development in rodents, but is under-investigated in humans. We investigated the association between one-carbon metabolism-related micronutrient intake and HCC risk in a prospective cohort of 494 860 participants with 16 years of follow-up in the NIH-AARP study. Dietary intakes and supplement use were ascertained at baseline using a food-frequency questionnaire. Total intake (diet plus supplements) of the following one-carbon metabolism-related micronutrients were calculated: folate, methionine and vitamins B2 (riboflavin), B3 (niacin), B6 and B12 . These micronutrients were examined both individually and simultaneously, with adjustment for covariates. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over the 16-year follow-up period, 647 incident HCC cases were diagnosed. When examined individually, higher total vitamin B3 intake was associated with a lower HCC risk (HRQ5 vs Q1 = 0.60; 95% CI = 0.42-0.85; Ptrend = .008), and the association remained significant when all six micronutrients were examined simultaneously (HRQ5 vs Q1 = 0.32; 95% CI = 0.18-0.55; Ptrend < .0001). Among participants with >3 years of follow-up, higher total vitamin B3 intake was again associated with lower risk (HRQ5 vs Q1 = 0.37; 95% CI = 0.20-0.68; Ptrend = .001), whereas higher total vitamin B6 intake was associated with higher risk (HRQ5 vs Q1 = 2.04; 95% CI = 1.02-4.07; Ptrend = .04). Restricted cubic spline analyses showed a dose-response inverse association between total vitamin B3 intake and HCC risk, and dose-response positive association between total vitamin B6 intake and HCC risk. The study suggests that higher vitamin B3 intake is associated with lower HCC risk, whereas higher vitamin B6 intake is associated with increased risk.

13.
Cancer Epidemiol Biomarkers Prev ; 29(7): 1423-1429, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32277007

RESUMO

BACKGROUND: A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated. METHODS: We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data from The Cancer Genome Atlas (TCGA) project. RESULTS: We identified seven independent SNPs in five lung CDGs that were consistently associated with lung cancer risk in discovery (P < 0.001) and validation (P < 0.05) stages. Among these loci, rs78062588 in TPM3 (1q21.3) was a new lung cancer susceptibility locus (OR = 0.86, P = 1.65 × 10-6). Subgroup analysis by histologic types further identified nine lung CDGs. Analysis of somatic alterations found that in lung adenocarcinomas, rs78062588[C] allele (TPM3 in 1q21.3) was associated with elevated somatic copy number of TPM3 (OR = 1.16, P = 0.02). In lung adenocarcinomas, rs1611182 (HLA-A in 6p22.1) was associated with truncation mutations of the transcriptional misregulation in cancer pathway (OR = 0.66, P = 1.76 × 10-3). CONCLUSIONS: Genetic variants can regulate functions of lung CDGs and influence lung cancer susceptibility. IMPACT: Our findings might help unravel biological mechanisms underlying lung cancer susceptibility.

14.
J Clin Oncol ; 38(18): 2018-2027, 2020 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-32250715

RESUMO

PURPOSE: To investigate the association of postdiagnosis body mass index (BMI) and weight change with prostate cancer-specific mortality (PCSM), cardiovascular disease-related mortality (CVDM), and all-cause mortality among survivors of nonmetastatic prostate cancer. METHODS: Men in the Cancer Prevention Study II Nutrition Cohort diagnosed with nonmetastatic prostate cancer between 1992 and 2013 were followed for mortality through December 2016. Current weight was self-reported on follow-up questionnaires approximately every 2 years. Postdiagnosis BMI was obtained from the first survey completed 1 to < 6 years after diagnosis. Weight change was the difference in weight between the first and second postdiagnosis surveys. Deaths occurring within 4 years of the follow-up were excluded to reduce bias from reverse causation. Analyses of BMI and weight change included 8,330 and 6,942 participants, respectively. RESULTS: Postdiagnosis BMI analyses included 3,855 deaths from all causes (PCSM, n = 500; CVDM, n = 1,155). Using Cox proportional hazards models, hazard ratios (HRs) associated with postdiagnosis obesity (BMI ≥ 30 kg/m2) compared with healthy weight (BMI 18.5 to < 25.0 kg/m2) were 1.28 for PCSM (95% CI, 0.96 to 1.67), 1.24 for CVDM (95% CI, 1.03 to 1.49), and 1.23 for all-cause mortality (95% CI, 1.11 to 1.35). Weight gain analyses included 2,973 deaths (PCSM, n = 375; CVDM, n = 881). Postdiagnosis weight gain (> 5% of body weight), compared with stable weight (± < 3%), was associated with a higher risk of PCSM (HR, 1.65; 95% CI, 1.21 to 2.25) and all-cause mortality (HR, 1.27; 95% CI, 1.12 to 1.45) but not CVDM. CONCLUSION: Results suggest that among survivors of nonmetastatic prostate cancer with largely localized disease, postdiagnosis obesity is associated with higher CVDM and all-cause mortality, and possibly higher PCSM, and that postdiagnosis weight gain may be associated with a higher mortality as a result of all causes and prostate cancer.

15.
Curr Fungal Infect Rep ; 14(1): 50-62, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32201545

RESUMO

Purpose of Review: This article aimed to review animal models of antifungals and identifies human literature to assess if the extrapolation of results is reliable. Recent Findings: Animal studies have helped identify AUC/MIC targets for new drugs and formulations such as isavuconazole and delayed release posaconazole that have translated to successful outcomes in humans. Models have also been influential in the identification of possible combination therapies for the treatment of aspergillosis, such as voriconazole and echinocandins. However, challenges are endured with animal models when it comes to replicating the pharmacokinetics of humans which has been exemplified with the newest itraconazole formulation. Additionally, animal models have displayed a survival benefit with the use of iron chelators and amphotericin for mucormycosis which was not demonstrated in humans. Summary: Animal models have been a staple in the development and optimization of antifungal agents. They afford the ability to investigate uncommon diseases, such as invasive fungal infections, that would otherwise take years and many resources to complete. Although there are many benefits of animal models there are also shortcomings. This is why the reliability of extrapolating data from animal models to humans is often scrutinized.

16.
Cancer Epidemiol Biomarkers Prev ; 29(5): 1029-1038, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32132146

RESUMO

BACKGROUND: Research on the relationship of meat, fish, and egg consumption and mortality among prostate cancer survivors is limited. METHODS: In the Cancer Prevention Study-II Nutrition Cohort, men diagnosed with nonmetastatic prostate cancer between baseline in 1992/1993 and 2015 were followed for mortality until 2016. Analyses of pre- and postdiagnosis intakes of red and processed meat, poultry, fish, and eggs included 9,286 and 4,882 survivors, respectively. Multivariable-adjusted RRs and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. RESULTS: A total of 4,682 and 2,768 deaths occurred during follow-up in pre- and postdiagnosis analyses, respectively. Both pre- and postdiagnosis intakes of total red and processed meat were positively associated with all-cause mortality (quartile 4 vs. 1: RR = 1.13; 95% CI, 1.03-1.25; P trend = 0.02; RR = 1.22; 95% CI, 1.07-1.39; P trend = 0.03, respectively), and both pre- and postdiagnosis poultry intakes were inversely associated with all-cause mortality (quartile 4 vs. 1 RR = 0.90; 95% CI, 0.82-0.98; P trend = 0.04; RR = 0.84; 95% CI, 0.75-0.95; P trend = 0.01, respectively). No associations were seen for prostate cancer-specific mortality, except that higher postdiagnosis unprocessed red meat intake was associated with lower risk. CONCLUSIONS: Higher red and processed meat, and lower poultry, intakes either before or after prostate cancer diagnosis were associated with higher risk of all-cause mortality. IMPACT: Our findings provide additional evidence that prostate cancer survivors should follow the nutrition guidelines limiting red and processed meat consumption to improve overall survival. Additional research on the relationship of specific meat types and mortality is needed.

17.
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.

18.
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
19.
Am J Epidemiol ; 189(2): 108-115, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-31602476

RESUMO

Higher body mass index (BMI; weight (kg)/height (m)2) is associated with increased risk of pancreatic cancer in epidemiologic studies. However, BMI has usually been assessed at older ages, potentially underestimating the full impact of excess weight. We examined the association between BMI and pancreatic cancer mortality among 963,317 adults who were aged 30-89 years at their enrollment in Cancer Prevention Study II in 1982. During follow-up through 2014, a total of 8,354 participants died of pancreatic cancer. Hazard ratios per 5 BMI units, calculated using proportional hazards regression, declined steadily with age at BMI assessment, from 1.25 (95% confidence interval: 1.18, 1.33) in persons aged 30-49 years at enrollment to 1.13 (95% confidence interval: 1.02, 1.26) in those aged 70-89 years at enrollment (P for trend = 0.005). On the basis of a hazard ratio of 1.25 per 5 BMI units at age 45 years, we estimated that 28% of US pancreatic cancer deaths among persons born in 1970-1974 will be attributable to BMI ≥25.0-nearly twice the equivalent proportion of those born in the 1930s, a birth cohort with much lower BMI in middle age. These results suggest that BMI before age 50 years is more strongly associated with pancreatic cancer risk than BMI at older ages, and they underscore the importance of avoiding excess weight gain before middle age for preventing this highly fatal cancer.


Assuntos
Fatores Etários , Índice de Massa Corporal , Neoplasias Pancreáticas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/fisiopatologia , Modelos de Riscos Proporcionais , Fatores de Risco
20.
Int J Cancer ; 146(10): 2855-2864, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31577861

RESUMO

Genome-wide association studies (GWAS) have identified 45 susceptibility loci associated with lung cancer. Only less than SNPs, small insertions and deletions (INDELs) are the second most abundant genetic polymorphisms in the human genome. INDELs are highly associated with multiple human diseases, including lung cancer. However, limited studies with large-scale samples have been available to systematically evaluate the effects of INDELs on lung cancer risk. Here, we performed a large-scale meta-analysis to evaluate INDELs and their risk for lung cancer in 23,202 cases and 19,048 controls. Functional annotations were performed to further explore the potential function of lung cancer risk INDELs. Conditional analysis was used to clarify the relationship between INDELs and SNPs. Four new risk loci were identified in genome-wide INDEL analysis (1p13.2: rs5777156, Insertion, OR = 0.92, p = 9.10 × 10-8 ; 4q28.2: rs58404727, Deletion, OR = 1.19, p = 5.25 × 10-7 ; 12p13.31: rs71450133, Deletion, OR = 1.09, p = 8.83 × 10-7 ; and 14q22.3: rs34057993, Deletion, OR = 0.90, p = 7.64 × 10-8 ). The eQTL analysis and functional annotation suggested that INDELs might affect lung cancer susceptibility by regulating the expression of target genes. After conducting conditional analysis on potential causal SNPs, the INDELs in the new loci were still nominally significant. Our findings indicate that INDELs could be potentially functional genetic variants for lung cancer risk. Further functional experiments are needed to better understand INDEL mechanisms in carcinogenesis.


Assuntos
Predisposição Genética para Doença/genética , Mutação INDEL/genética , Neoplasias Pulmonares/genética , Estudo de Associação Genômica Ampla , Humanos
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