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1.
Int J Cancer ; 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31469419

RESUMO

Women of African Ancestry have lower incidence of epithelial ovarian cancer (EOC) yet worse survival compared to women of European Ancestry. We conducted a genome-wide association study (GWAS) in African ancestry women with 755 EOC cases, including 537 high-grade serous ovarian carcinomas (HGSOC), and 1,235 controls. We identified four novel loci with suggestive evidence of association with EOC (P < 1x10-6 ), including rs4525119 (intronic to AKR1C3), rs7643459 (intronic to LOC101927394), rs4286604 (12 kb 3' of UGT2A2), and rs142091544 (5 kb 5' of WWC1). For HGSOC, we identified six loci with suggestive evidence of association including rs37792 (132 kb 5' of FST), rs57403204 (81 kb 3' of MAGEC1), rs79079890 (LOC105376360 intronic), rs66459581 (5 kb 5' of PRPSAP1), rs116046250 (GABRG3 intronic), and rs192876988 (32 kb 3' of GK2). Among the identified variants, two are near genes known to regulate hormones and diseases of the ovary (AKR1C3 and FST), and two are linked to cancer (AKR1C3 and MAGEC1). In follow-up studies of the 10 identified variants, the GK2 region SNP, rs192876988, showed an inverse association with EOC in European ancestry women (P = 0.002), increased risk of ER positive breast cancer in African ancestry women (P = 0.027), and decreased expression of GK2 in HGSOC tissue from African ancestry women (P = 0.004). A European ancestry-derived polygenic risk score showed positive associations with EOC and HGSOC in women of African ancestry suggesting shared genetic architecture. Our investigation presents evidence of variants for EOC shared among European and African ancestry women and identifies novel EOC risk loci in women of African ancestry. This article is protected by copyright. All rights reserved.

2.
J Am Coll Nutr ; : 1-8, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291155

RESUMO

Objective: To understand how diet quality affects chronic disease etiology, the associations of 4 a priori diet quality indices with blood levels of lipid-soluble micronutrients and biomarkers of inflammation, lipid, and glucose metabolism were examined in 5 ethnic groups. Methods: In a cross-sectional design, the Adiposity Phenotype Study, a subset of the Multiethnic Cohort in Hawaii and Los Angeles, recruited participants of white, African American, Native Hawaiian, Japanese American, and Latino ancestry. A total of 896 men and 910 women completed a validated quantitative food frequency questionnaire and anthropometric measurements and donated a fasting blood sample. Using general linear models, covariate-adjusted mean levels of lipid-soluble micronutrients (total carotenes, lycopene, total tocopherols, total lutein, cryptoxanthins), biomarkers of inflammation (C-reactive protein [CRP], tumor necrosis factor- α ), adipokines (adiponectin, leptin), lipids (total cholesterol, high-density lipoprotein cholesterol [HDL-C], triglycerides), and glucose metabolism (glucose, insulin, homeostatic model assessment of insulin resistance [HOMA-IR]) were computed across tertiles of 4 a priori dietary indices Healthy Eating Index (HEI)-2010, Alternative HEI (AHEI)-2010, alternate Mediterranean Diet (aMED), Dietary Approaches to Stop Hypertension (DASH); trends were evaluated in models with diet quality scores as continuous variables. Results: With better diet quality, levels of carotenes, lutein, cryptoxanthin, adiponectin, and HDL-C were significantly higher (ptrend < 0.01), whereas levels of CRP, leptin, total cholesterol, triglycerides, glucose, insulin, and HOMA-IR were inversely associated (ptrend < 0.05) with diet quality. With the exception of cryptoxanthins and triglycerides, the associations were consistent across ethnic groups. Conclusions: These findings confirm the association between diet quality and nutrition-related biomarkers and support the idea that a high-quality diet positively influences biologic pathways involved in chronic disease etiology across different ethnic groups.

3.
Int J Cancer ; 2019 Jul 05.
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.

4.
Eur J Clin Nutr ; 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31243335

RESUMO

BACKGROUND/OBJECTIVES: γ-Tocopherol has unique properties that protect against nitrogen oxide-mediated cellular damage. To elucidate the potential role of γ-tocopherol in the aging process, we examined the associations of serum γ-tocopherol levels with all-cause and cause-specific mortality. SUBJECTS/METHODS: Among participants in the biorepository subcohort of the Multiethnic Cohort Study, pre-cancer diagnostic serum γ-tocopherol levels were measured in a subset of 3904 men and 4461 women. Of these, 22.7% of men and 13.5% of women died during a mean follow-up time of 9.6 ± 2.6 years. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for mortality associated with γ-tocopherol were estimated by Cox proportional hazards regression. RESULTS: Positive associations of serum γ-tocopherol with all-cause, cancer, and cardiovascular disease mortality (CVD) (Ptrend < 0.05) were detected after adjusting for age, race/ethnicity, and serum cholesterol levels. The respective HRs (95% CIs) for the highest versus the lowest sex-specific γ-tocopherol quartile were 1.43 (1.17-1.74), 1.79 (1.22-2.64), and 1.52 (1.10-2.11) for men and 1.58 (1.25-2.00), 1.59 (1.05-2.41), and 1.59 (1.07-2.37) for women. Associations remained significant for all-cause mortality among women after further adjusting for smoking variables and history of cancer, CVD, diabetes, and hypertension at cohort entry (highest vs. lowest γ-tocopherol quartile: HR = 1.38; 95% CI = 1.08-1.75; Ptrend = 0.005). Overall, associations with all-cause mortality were consistent across race/ethnicity and were significant in three of ten sex-specific racial/ethnic groups in the fully adjusted models, with no interactions between ethnicity and γ-tocopherol. CONCLUSIONS: The positive association between γ-tocopherol and mortality suggests a potential physiological role for γ-tocopherol in response to pathological conditions.

5.
J Nutr ; 149(9): 1575-1584, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31187868

RESUMO

BACKGROUND: Variation in gut microbial community structure is partly attributed to variations in diet. A priori dietary indexes capture diet quality and have been associated with chronic disease risk. OBJECTIVES: The aim of this study was to examine the association of diet quality, as assessed by the Healthy Eating Index, Alternative Healthy Eating Index-2010, alternate Mediterranean Diet, and the Dietary Approaches to Stop Hypertension Trial, with measures of fecal microbial community structure assessed in the Adiposity Phenotype Study (APS), an ethnically diverse study population with varied food intakes. METHODS: Multiethnic Cohort Study members completed a validated quantitative food frequency questionnaire (QFFQ) at cohort entry (1993-1996) and, for the APS subset, at clinic visit (2013-2015), when they also provided a stool sample. DNA was extracted from stool, and the V1-V3 region of the 16S rRNA gene was amplified and sequenced. Dietary index scores were computed based on the QFFQ and an extensive nutritional database. Using linear regression adjusted for relevant covariates, we estimated associations of dietary quality with microbiome measures and computed adjusted mean values of microbial measures by tertiles of dietary index scores. RESULTS: The 858 men and 877 women of white, Japanese American, Latino, Native Hawaiian, and African American ancestry had a mean age of 69.2 years at stool collection. Alpha diversity according to the Shannon index increased by 1-2% across tertiles of all 4 diet indexes measured at clinic visit. The mean relative abundance of the phylum Actinobacteria was 13-19% lower with higher diet quality across all 4 indexes (difference between tertile 3 and tertile 1 divided by tertile 1). Of the 104 bacterial genera tested, 21 (primarily from the phylum Firmicutes) were positively associated with at least 1 index after Bonferroni adjustment. CONCLUSION: Diet quality was strongly associated with fecal microbial alpha diversity and beta diversity and several genera previously associated with human health.

6.
J Thorac Oncol ; 14(9): 1594-1607, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31163278

RESUMO

INTRODUCTION: The relationships between morbid obesity, changes in body mass index (BMI) before cancer diagnosis, and lung cancer outcomes by histology (SCLC and NSCLC) have not been well studied. METHODS: Individual level data analysis was performed on 25,430 patients with NSCLC and 2787 patients with SCLC from 16 studies of the International Lung Cancer Consortium evaluating the association between various BMI variables and lung cancer overall survival, reported as adjusted hazard ratios (aHRs) from Cox proportional hazards models and adjusted penalized smoothing spline plots. RESULTS: Overall survival of NSCLC had putative U-shaped hazard ratio relationships with BMI based on spline plots: being underweight (BMI < 18.5 kg/m2; aHR = 1.56; 95% confidence interval [CI]:1.43-1.70) or morbidly overweight (BMI > 40 kg/m2; aHR = 1.09; 95% CI: 0.95-1.26) at the time of diagnosis was associated with worse stage-specific prognosis, whereas being overweight (25 kg/m2 ≤ BMI < 30 kg/m2; aHR = 0.89; 95% CI: 0.85-0.95) or obese (30 kg/m2 ≤ BMI ≤ 40 kg/m2; aHR = 0.86; 95% CI: 0.82-0.91) was associated with improved survival. Although not significant, a similar pattern was seen with SCLC. Compared with an increased or stable BMI from the period between young adulthood until date of diagnosis, a decreased BMI was associated with worse outcomes in NSCLC (aHR = 1.24; 95% CI: 1.2-1.3) and SCLC patients (aHR=1.26 (95% CI: 1.0-1.6). Decreased BMI was consistently associated with worse outcome, across clinicodemographic subsets. CONCLUSIONS: Both being underweight or morbidly obese at time of diagnosis is associated with lower stage-specific survival in independent assessments of NSCLC and SCLC patients. In addition, a decrease in BMI at lung cancer diagnosis relative to early adulthood is a consistent marker of poor survival.

7.
Am J Epidemiol ; 188(6): 991-1012, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31155658

RESUMO

The Consortium of Metabolomics Studies (COMETS) was established in 2014 to facilitate large-scale collaborative research on the human metabolome and its relationship with disease etiology, diagnosis, and prognosis. COMETS comprises 47 cohorts from Asia, Europe, North America, and South America that together include more than 136,000 participants with blood metabolomics data on samples collected from 1985 to 2017. Metabolomics data were provided by 17 different platforms, with the most frequently used labs being Metabolon, Inc. (14 cohorts), the Broad Institute (15 cohorts), and Nightingale Health (11 cohorts). Participants have been followed for a median of 23 years for health outcomes including death, cancer, cardiovascular disease, diabetes, and others; many of the studies are ongoing. Available exposure-related data include common clinical measurements and behavioral factors, as well as genome-wide genotype data. Two feasibility studies were conducted to evaluate the comparability of metabolomics platforms used by COMETS cohorts. The first study showed that the overlap between any 2 different laboratories ranged from 6 to 121 metabolites at 5 leading laboratories. The second study showed that the median Spearman correlation comparing 111 overlapping metabolites captured by Metabolon and the Broad Institute was 0.79 (interquartile range, 0.56-0.89).

9.
Int J Cancer ; 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31209889

RESUMO

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10-6 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10-6 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10-6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.

10.
Nutrients ; 11(6)2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31226790

RESUMO

Intermittent energy restriction combined with a Mediterranean diet (IER+MED) has shown promise to reduce body fat and insulin resistance. In the Multiethnic Cohort Adiposity Phenotype Study, Japanese Americans had the highest visceral adipose tissue (VAT) when adjusting for total adiposity. We conducted this pilot study to demonstrate feasibility and explore efficacy of following IER+MED for 12 weeks to reduce VAT among East Asians in Hawaii. Sixty volunteers (aged 35-55, BMI 25-40 kg/m2, VAT ≥ 90 cm2 for men and ≥ 80 cm2 for women) were randomized to IER+MED (two consecutive days with 70% energy restriction and 5 days euenergetic MED) or an active comparator (euenergetic Dietary Approaches to Stop Hypertension (DASH) diet). Participants and clinic staff (except dietitians) were blinded to group assignments. IER+MED had significantly larger reductions in DXA-measured VAT and total fat mass (-22.6 ± 3.6 cm2 and -3.3 ± 0.4 kg, respectively) vs. DASH (-10.7 ± 3.5 cm2 and -1.6 ± 0.4 kg) (p = 0.02 and p = 0.005). However, after adjusting for total fat mass, change in VAT was not statistically different between groups; whereas, improvement in alanine transaminase remained significantly greater for IER+MED vs. DASH (-16.2 ± 3.8 U/L vs. -4.0 ± 3.6 U/L, respectively, p = 0.02). Attrition rate was 10%, and participants adhered well to study prescriptions with no reported major adverse effect. Results demonstrate IER+MED is acceptable, lowers visceral and total adiposity among East Asian Americans, and may improve liver function more effectively than a healthful diet pattern. ClinicalTrials.gov Identifier: NCT03639350.

11.
Breast Cancer Res ; 21(1): 68, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118087

RESUMO

BACKGROUND: Mammographic breast density, adjusted for age and body mass index, and a polygenic risk score (PRS), comprised of common genetic variation, are both strong risk factors for breast cancer and increase discrimination of risk models. Understanding their joint contribution will be important to more accurately predict risk. METHODS: Using 3628 breast cancer cases and 5126 controls of European ancestry from eight case-control studies, we evaluated joint associations of a 77-single nucleotide polymorphism (SNP) PRS and quantitative mammographic density measures with breast cancer. Mammographic percent density and absolute dense area were evaluated using thresholding software and examined as residuals after adjusting for age, 1/BMI, and study. PRS and adjusted density phenotypes were modeled both continuously (per 1 standard deviation, SD) and categorically. We fit logistic regression models and tested the null hypothesis of multiplicative joint associations for PRS and adjusted density measures using likelihood ratio and global and tail-based goodness of fit tests within the subset of six cohort or population-based studies. RESULTS: Adjusted percent density (odds ratio (OR) = 1.45 per SD, 95% CI 1.38-1.52), adjusted absolute dense area (OR = 1.34 per SD, 95% CI 1.28-1.41), and the 77-SNP PRS (OR = 1.52 per SD, 95% CI 1.45-1.59) were associated with breast cancer risk. There was no evidence of interaction of the PRS with adjusted percent density or dense area on risk of breast cancer by either the likelihood ratio (P > 0.21) or goodness of fit tests (P > 0.09), whether assessed continuously or categorically. The joint association (OR) was 2.60 in the highest categories of adjusted PD and PRS and 0.34 in the lowest categories, relative to women in the second density quartile and middle PRS quintile. CONCLUSIONS: The combined associations of the 77-SNP PRS and adjusted density measures are generally well described by multiplicative models, and both risk factors provide independent information on breast cancer risk.

12.
Cancer Med ; 8(7): 3592-3603, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31066497

RESUMO

While disparity in pancreatic cancer incidence between blacks and whites has been observed, few studies have examined disparity in other ethnic minorities. We evaluated variations in pancreatic cancer incidence and assessed the extent to which known risk factors account for differences in pancreatic cancer risk among African Americans, Native Hawaiians, Japanese Americans, Latino Americans, and European Americans in the Multiethnic Cohort Study. Risk factor data were obtained from the baseline questionnaire. Cox regression was used to estimate the relative risks (RRs) and 95% confidence intervals (CIs) for pancreatic cancer associated with risk factors and ethnicity. During an average 16.9-year follow-up, 1,532 incident pancreatic cancer cases were identified among 184,559 at-risk participants. Family history of pancreatic cancer (RR 1.97, 95% CI 1.50-2.58), diabetes (RR 1.32, 95% CI 1.14-1.54), body mass index ≥30 kg/m2 (RR 1.25, 95% CI 1.08-1.46), current smoking (<20 pack-years RR 1.43, 95% CI 1.19-1.73; ≥20 pack-years RR 1.76, 95% CI 1.46-2.12), and red meat intake (RR 1.17, 95% CI 1.00-1.36) were associated with pancreatic cancer. After adjustment for these risk factors, Native Hawaiians (RR 1.60, 95% CI 1.30-1.98), Japanese Americans (RR 1.33, 95% CI 1.15-1.54), and African Americans (RR 1.20, 95% CI 1.01-1.42), but not Latino Americans (RR 0.90, 95% CI 0.76-1.07), had a higher risk of pancreatic cancer compared to European Americans. Interethnic differences in pancreatic cancer risk are not fully explained by differences in the distribution of known risk factors. The greater risks in Native Hawaiians and Japanese Americans are new findings and elucidating the causes of these high rates may improve our understanding and prevention of pancreatic cancer.

13.
Int J Cancer ; 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31037736

RESUMO

Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.

14.
J Thorac Oncol ; 14(8): 1360-1369, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31009812

RESUMO

INTRODUCTION: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. METHODS: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. RESULTS: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 × 10-16), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 × 10-16), and rs4975616 (OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 × 10-14). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. CONCLUSIONS: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.

15.
Clin Mol Hepatol ; 2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31001964

RESUMO

Background/Aims: Inflammation-based scores, such as the neutrophil-to-lymphocyte ratio (NLR), have been associated with prognosis in hepatocellular carcinoma (HCC); but variable cut-off values and potential lack of specificity have limited the utility of NLR. This study evaluates NLR in a large cohort of HCC patients. Methods: We retrospectively reviewed 789 HCC cases (1993-2017) for demographics, tumor characteristics, treatment, and survival. NLR was stratified into NLR ≥1.5 and NLR ≥3 and analyzed for correlation with American Joint Committee on Cancer (AJCC) and Barcelona Clinic Liver Cancer (BCLC) stages. In 235 patients who underwent liver resection, survival and recurrence were evaluated by NLR. Results: In 789 HCC cases, mean NLR was increased with advanced AJCC and BCLC stages. Hepatitis C patients were less likely to have NLR ≥1.5 and ≥3. Non-alcoholic steatohepatitis patients were more likely to have NLR ≥3. Patients with tumor size >5 cm, rupture, or macrovascular invasion were more likely to have NLR ≥3. In patients treated with resection, NLR ≥3 predicted early recurrence (odds ratio [OR] 4.14, P<0.01) and overall recurrence (OR 4.05, P<0.01). Mean NLR was 4.30 in those with recurrence and 2.75 in those without recurrence. Patients with NLR ≥3 showed significantly worse survival compared to those with NLR <3 (P<0.01 by log-rank test). Conclusions: Elevated NLR is associated with advanced cancer stage and aggressive tumor characteristics, such as large size, rupture, and invasion. NLR ≥3 was associated with early and overall recurrence after resection but varied with etiology. NLR may be a useful biomarker in predicting recurrence for HCC patients undergoing curative resection, but further studies are required to elucidate the effect of disease etiology.

16.
Cancer Med ; 8(5): 2503-2513, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31001917

RESUMO

An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom-designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high-grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 1.2 × 10-6 , BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6-3.4, P = 1.6 × 10-5 , BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 2.3 × 10-5 , BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.

17.
Int J Cancer ; 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30924138

RESUMO

Previous studies using different exposure methods to assess air pollution and breast cancer risk among primarily whites have been inconclusive. Air pollutant exposures of particulate matter and oxides of nitrogen were estimated by kriging (NOx , NO2 , PM10 , PM2.5 ), land use regression (LUR, NOx , NO2 ) and California Line Source Dispersion model (CALINE4, NOx , PM2.5 ) for 57,589 females from the Multiethnic Cohort, residing largely in Los Angeles County from recruitment (1993-1996) through 2010. Cox proportional hazards models were used to examine the associations between time-varying air pollution and breast cancer incidence adjusting for confounding factors. Stratified analyses were conducted by race/ethnicity and distance to major roads. Among all women, breast cancer risk was positively but not significantly associated with NOx (per 50 parts per billion [ppb]) and NO2 (per 20 ppb) determined by kriging and LUR and with PM2.5 and PM10 (per 10 µg/m3 ) determined by kriging. However, among women who lived within 500 m of major roads, significantly increased risks were observed with NOx (hazard ratio [HR] = 1.35, 95% confidence interval [95% CI]: 1.02-1.79), NO2 (HR = 1.44, 95% CI: 1.04-1.99), PM10 (HR = 1.29, 95% CI: 1.07-1.55) and PM2.5 (HR = 1.85, 95% CI: 1.15-2.99) determined by kriging and NOx (HR = 1.21, 95% CI:1.01-1.45) and NO2 (HR = 1.26, 95% CI: 1.00-1.59) determined by LUR. No overall associations were observed with exposures assessed by CALINE4. Subgroup analyses suggested stronger associations of NOx and NO2 among African Americans and Japanese Americans. Further studies of multiethnic populations to confirm the effects of air pollution, particularly near-roadway exposures, on the risk of breast cancer is warranted.

18.
Int J Cancer ; 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30873591

RESUMO

Insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross-sectional associations of these exposures with circulating concentrations of IGFs (IGF-I and IGF-II) and IGFBPs (IGFBP-1, IGFBP-2 and IGFBP-3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22-89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGF-I, IGF-II and IGFBP-3. Higher body mass index was associated with lower concentrations of IGFBP-1 and IGFBP-2. Taller height was associated with higher concentrations of IGF-I and IGFBP-3 and lower concentrations of IGFBP-1. Smokers had higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGFBP-3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF-II and lower concentrations of IGF-I and IGFBP-2. African Americans had lower concentrations of IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 and Hispanics had lower IGF-I, IGF-II and IGFBP-3 than non-Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk.

19.
Hum Genet ; 138(4): 307-326, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30820706

RESUMO

Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n = 169) and whole blood (n = 922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR ≤ 0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P = 2.2 × 10- 4, replication P = 0.01), and PYGL (discovery P = 2.3 × 10- 4, replication P = 6.7 × 10- 4). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P < 0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.


Assuntos
Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Neoplasias Colorretais/epidemiologia , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Frequência do Gene , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco
20.
Int J Cancer ; 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30895617

RESUMO

Breast cancer is the most common cancer and the second-leading cause of cancer-related death among women. Inconsistent findings for the relationship between melatonin levels, sleep duration and breast cancer have been reported. We investigated the association of sleep duration at cohort entry and its interaction with body mass index (BMI) with risk of developing breast cancer in the large population-based Multiethnic Cohort study. Among the 74,481 at-risk participants, 5,790 breast cancer cases were identified during the study period. Although we detected no significant association between sleep duration and breast cancer incidence, higher risk estimates for short (HR = 1.03; 95% CI: 0.97-1.09) and long sleep (HR = 1.05; 95% CI: 0.95-1.15) compared to normal sleep (7-8 hr) were found. The patterns for models stratified by age, BMI, ethnicity and hormone receptor status were similar but did not indicate significant interaction effects. When examining the combined sleep duration and BMI interaction effect, in comparison to the normal BMI-normal sleep group, risk estimates for underweight, overweight and obesity were similar across categories of sleep duration (≤6, 7-8, and ≥9 hr). The underweight-normal sleep group had lower breast cancer incidence (HR = 0.66, 95% CI: 0.50-0.86), whereas the overweight-short sleep, overweight-normal sleep group and all obese women experienced elevated breast cancer incidence. The respective HRs for short, normal and long sleep among obese women were 1.35 (95% CI: 1.20-1.53), 1.27 (95% CI: 1.15-1.42) and 1.46 (95% CI: 1.21-1.76). Future perspectives need to examine the possibility that sleep quality, variations in circadian rhythm and melatonin are involved in breast cancer etiology.

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