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1.
Sci Total Environ ; 773: 144708, 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33582339

RESUMO

Conflicts often exist between the use of pesticides for public health protection and organic farming. A prominent example is the use of insecticides for mosquito control in rice fields designated for organic farming. Rice fields, with static water and other conducive conditions, are favorable mosquito habitats. Best management practices are urgently needed to ensure the integrity of organic farming while addressing the need for public health protection. In this study, we evaluated aerial ultra-low-volume (ULV) applications of two classes of mosquito adulticides, pyrethrins and organophosphates, and their deposition and residues on rice plants throughout an active growing season in the Sacramento Valley of California. Frequent applications of pyrethrin synergized with piperonyl butoxide (PBO) and rotating applications of synergized pyrethrins and naled, an organophosphate, were carried out on two large blocks of rice fields. Aerial ULV application of either synergized pyrethrins or naled was able to generate uniform droplets above the fields with high efficacy for mosquito control. Rice leaf samples were collected before and after a subset of applications, and rice grains were sampled at harvest. Frequent applications of synergized pyrethrins resulted in some accumulation of the synergist PBO on rice leaves, but pyrethrins and naled dissipated rapidly from the leaves after each application with no noticeable accumulation over repeated applications. At harvest, no detectable residues of the pesticides or PBO were found in the rice grains. The absence of pesticide residues in the rice grains at harvest suggested that the ULV aerial application led to deposition of only very low levels of residues on rice plants during the growing season. When coupled with the short persistence and/or poor mobility of the insecticides, such applications resulted in negligible pesticide residues in rice grains.

2.
Lung Cancer ; 152: 58-65, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33352384

RESUMO

INTRODUCTION: The relationship between Body-Mass-Index (BMI) and lung cancer prognosis is heterogeneous. We evaluated the impact of sex, smoking and race on the relationship between BMI and overall survival (OS) in non-small-cell-lung-cancer (NSCLC). METHODS: Data from 16 individual ILCCO studies were pooled to assess interactions between BMI and the following factors on OS: self-reported race, smoking status and sex, using Cox models (adjusted hazard ratios; aHR) with interaction terms and adjusted penalized smoothing spline plots in stratified analyses. RESULTS: Among 20,937 NSCLC patients with BMI values, females = 47 %; never-smokers = 14 %; White-patients = 76 %. BMI showed differential survival according to race whereby compared to normal-BMI patients, being underweight was associated with poor survival among white patients (OS, aHR = 1.66) but not among black patients (aHR = 1.06; pinteraction = 0.02). Comparing overweight/obese to normal weight patients, Black NSCLC patients who were overweight/obese also had relatively better OS (pinteraction = 0.06) when compared to White-patients. BMI was least associated with survival in Asian-patients and never-smokers. The outcomes of female ever-smokers at the extremes of BMI were associated with worse outcomes in both the underweight (pinteraction<0.001) and obese categories (pinteraction = 0.004) relative to the normal-BMI category, when compared to male ever-smokers. CONCLUSION: Underweight and obese female ever-smokers were associated with worse outcomes in White-patients. These BMI associations were not observed in Asian-patients and never-smokers. Black-patients had more favorable outcomes in the extremes of BMI when compared to White-patients. Body composition in Black-patients, and NSCLC subtypes more commonly seen in Asian-patients and never-smokers, may account for differences in these BMI-OS relationships.

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.
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.

5.
BMC Cancer ; 20(1): 905, 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32962699

RESUMO

BACKGROUND: A low level of methylation at cg05575921 in the aryl-hydrocarbon receptor repressor (AHRR) gene is robustly associated with smoking, and some studies have observed associations between cg05575921 methylation and increased lung cancer risk and mortality. To prospectively examine whether decreased methylation at cg05575921 may identify high risk subpopulations for lung cancer screening among heavy smokers, and mortality in cases, we evaluated associations between cg05575921 methylation and lung cancer risk and mortality, by histotype, in heavy smokers. METHODS: The ß-Carotene and Retinol Efficacy Trial (CARET) included enrollees ages 45-69 with ≥ 20 pack-year smoking histories and/or occupational asbestos exposure. A subset of CARET participants had cg05575921 methylation available from HumanMethylationEPIC assays of blood collected on average 4.3 years prior to lung cancer diagnosis in cases. Cg05575921 methylation ß-values were treated continuously for a 10% methylation decrease and as quintiles, where quintile 1 (Q1, referent) represents high methylation and Q5, low methylation. We used conditional logistic regression models to examine lung cancer risk overall and by histotype in a nested case-control study including 316 lung cancer cases (diagnosed through 2005) and 316 lung cancer-free controls matched on age (±5 years), sex, race/ethnicity, enrollment year, current/former smoking, asbestos exposure, and follow-up time. Mortality analyses included 372 lung cancer cases diagnosed between 1985 and 2013 with available methylation data. We used Cox proportional hazards models to examine mortality overall and by histotype. RESULTS: Decreased cg05575921 methylation was strongly associated with smoking, even in our population of heavy smokers. We did not observe associations between decreased pre-diagnosis cg05575921 methylation and increased lung cancer risk, overall or by histotype. We observed linear increasing trends for lung cancer-specific mortality across decreasing cg05575921 methylation quintiles for adenocarcinoma and small cell carcinoma (P-trends = 0.01 and 0.04, respectively). CONCLUSIONS: In our study of heavy smokers, decreased cg05575921 methylation was strongly associated with smoking but not increased lung cancer risk. The observed association between cg05575921 methylation and increased mortality in adenocarcinoma and small cell histotypes requires further examination. Our results do not support using decreased cg05575921 methylation as a biomarker for lung cancer screening risk stratification.

6.
Genet Epidemiol ; 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32924180

RESUMO

Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1ß pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-κB signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.

7.
Int J Cancer ; 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32914876

RESUMO

At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes based on an aggregated genome-wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small-cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24-2.06, P = 2.70 × 10-4 ). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (ORMVMR = 1.28, 95% CI = 1.06-1.55, PMVMR = .011), and an inverse effect on lung adenocarcinoma (ORMVMR = 0.86, 95% CI = 0.77-0.96, PMVMR = .008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (ORUVMR = 1.19, 95% CI = 1.01-1.40, PUVMR = .036), but this effect disappeared after adjustment of smoking (ORMVMR = 1.02, 95% CI = 0.90-1.16, PMVMR = .746). These results highlight the histology-specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer.

8.
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.

9.
J Natl Cancer Inst ; 112(10): 1003-1012, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31917448

RESUMO

BACKGROUND: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. METHODS: To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74-421 samples). RESULTS: We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate < .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. CONCLUSIONS: By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

10.
Nat Commun ; 11(1): 27, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911640

RESUMO

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: rg = 0.098, p = 2.3 × 10-8) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: rg = 0.137, p = 2.0 × 10-12). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.


Assuntos
Neoplasias Pulmonares/genética , Pulmão/fisiopatologia , Adulto , Idoso , Feminino , Volume Expiratório Forçado , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/fisiopatologia , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Testes de Função Respiratória , Capacidade Vital
11.
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
12.
Int J Cancer ; 146(7): 1862-1878, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31696517

RESUMO

We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome-wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never- and ever-smokers). We performed replication analysis using lung data from the Genotype-Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever-smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (pTWAS = 1.09E-99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (pTWAS = 3.72E-6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3-adenocarcinoma on 9p13.3 was replicated using GTEx (pTWAS = 6.55E-5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk.


Assuntos
Biomarcadores Tumorais , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Pulmonares/genética , Transcriptoma , Linhagem Celular Tumoral , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
13.
Cancer Epidemiol Biomarkers Prev ; 28(7): 1228-1237, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31263055

RESUMO

BACKGROUND: Lung cancer remains the leading cause of cancer mortality with relatively few prognostic biomarkers. We investigated associations with overall survival for telomere length (TL) and genetic variation in chromosome 5p15.33, an established telomere maintenance locus. METHODS: Leukocyte TL was measured after diagnosis in 807 patients with non-small cell lung cancer (NSCLC) from the Princess Margaret Cancer Center in Toronto and assessed prospectively in 767 NSCLC cases from the Copenhagen City Heart Study and the Copenhagen General Population Study. Associations with all-cause mortality were tested for 723 variants in 5p15.33, genotyped in 4,672 NSCLC cases. RESULTS: Short telomeres (≤10th percentile) were associated with poor prognosis for adenocarcinoma in both populations: TL measured 6 months after diagnosis [HR = 1.65; 95% confidence intervals (CI), 1.04-2.64] and for those diagnosed within 5 years after blood sampling (HR = 2.42; 95% CI, 1.37-4.28). Short TL was associated with mortality in never smokers with NSCLC (HR = 10.29; 95% CI, 1.86-56.86) and adenocarcinoma (HR = 11.31; 95% CI, 1.96-65.24). Analyses in 5p15.33 identified statistically significant prognostic associations for rs56266421-G in LPCAT1 (HR = 1.86; 95% CI, 1.38-2.52; P = 4.5 × 10-5) in stage I-IIIA NSCLC, and for the SLC6A3 gene with OS in females with NSCLC (P = 1.6 × 10-3). CONCLUSIONS: Our findings support the potential clinical utility of TL, particularly for adenocarcinoma patients, while associations in chromosome 5p15.33 warrant further exploration. IMPACT: This is the largest lung cancer study of leukocyte TL and OS, and the first to examine the impact of the timing of TL measurement. Our findings suggest that extremely short telomeres are indicative of poor prognosis in NSCLC.


Assuntos
Variação Genética/genética , Leucócitos/metabolismo , Neoplasias Pulmonares/genética , Telômero/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco
14.
J Thorac Oncol ; 14(9): 1594-1607, 2019 09.
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.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Neoplasias Pulmonares/fisiopatologia , Carcinoma de Pequenas Células do Pulmão/fisiopatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Carcinoma de Pequenas Células do Pulmão/mortalidade , Análise de Sobrevida , Adulto Jovem
15.
Cancer Prev Res (Phila) ; 12(7): 481-490, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31138522

RESUMO

Observational studies have reported an inverse association between vitamin D intake and breast cancer risk. We examined whether vitamin D supplementation in high-risk premenopausal women reduces mammographic density (MD), an established breast cancer risk factor. We conducted a multicenter randomized double-blind placebo-controlled trial in premenopausal women at high risk for breast cancer [5-year risk ≥ 1.67%, lifetime risk ≥ 20%, lobular carcinoma in situ, prior stage 0-II breast cancer, hereditary breast cancer syndrome, or high MD (heterogeneously/extremely dense)], with a baseline serum 25-hydroxyvitamin D [25(OH)D] ≤ 32 ng/mL. Participants were randomized to 12 months of vitamin D3 20,000 IU/week or matching placebo. The primary endpoint was change in MD from baseline to 12 months using the Cumulus technique. Secondary endpoints included serial blood biomarkers [25(OH)D, 1,25-dihydroxyvitamin D (1,25(OH)D), insulin-like growth factor (IGF)-1, IGF-binding protein-3] and MD change at 24 months. Among 208 women randomized, median age was 44.6 years, 84% were white, 33% had baseline 25(OH)D < 20 ng/mL, and 78% had high baseline MD. Comparing the active and placebo groups at 12 months, MD changes were small and did not significantly differ. Mean MD changes at 12 and 24 months were -0.3% and -1.2%, respectively, in the active arm and +1.5% and +1.6% with placebo (P > 0.05). We observed a mean change in serum 25(OH)D of +18.9 versus +2.8 ng/mL (P < 0.01) and IGF-1 of -9.8 versus -1.8 ng/mL (P = 0.28), respectively. At 12 months, MD was positively correlated with serum IGF-1 and IGF-1/IGFBP-3 (P < 0.01). This trial does not support the use of vitamin D supplementation for breast cancer risk reduction.


Assuntos
Biomarcadores/sangue , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Lobular/tratamento farmacológico , Suplementos Nutricionais , Pré-Menopausa , Vitamina D/análogos & derivados , Adulto , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/sangue , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/sangue , Carcinoma Lobular/patologia , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Hiperplasia/sangue , Hiperplasia/tratamento farmacológico , Hiperplasia/patologia , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/análise , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Vitamina D/administração & dosagem
16.
Oncotarget ; 10(19): 1760-1774, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30956756

RESUMO

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.

17.
Int J Gynecol Cancer ; 2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30700568

RESUMO

OBJECTIVE: Our goals were to: establish the maximum-tolerated dose of olaparib tablets combined with metronomic carboplatin and paclitaxel in patients with relapsed high-grade serous ovarian cancer; evaluate dose-limiting toxicities; and evaluate efficacy at the maximum tolerated dose. METHODS: In this open-label, single-arm, investigator-initiated trial (ClinicalTrials.gov NCT01650376), patients with high-grade serous ovarian cancer who failed primary platinum and taxane therapy received oral olaparib tablets twice daily days 1-3 each week combined with fixed-dose metronomic carboplatin AUC2 and paclitaxel 60 mg/m2 weekly for 3 out of 4 weeks. A 3 × 3 design was used to determine the olaparib maximum tolerated dose. Combination therapy continued until disease progression, but patients with partial or complete response were transitioned to olaparib maintenance therapy. All patients were included in the analysis. RESULTS: The maximum tolerated dose of olaparib tablets was 150 mg twice daily with metronomic carboplatin and paclitaxel. 54 women were enrolled, 14 in phase Ib and 40 in the expansion phase. The median number of prior therapeutic regimens was 3. Response included 13 complete remission (24%) and 16 partial remission (30%) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for an overall response rate of 54% (95% CI 40% to 67%). Of 47 patients who underwent BRCA testing, 23 were BRCA mutation (BRCAm) and 24 B RCA wild type (BRCAwt). Progression-free survival for BRCAm was 12.1 months versus 4.8 for BRCAwt (p=0.0001). Median overall survival for BRCAm was 24.1 months versus 10.4 months for BRCAwt (p=0.02). 42 patients (78%) experienced grade 3-4 toxicities with combination therapy; the most common were hematologic. There were no treatment related deaths. Among 14 patients who received maintenance therapy, 7 experienced grade 1-2 non-hematologic toxicities. CONCLUSIONS: Olaparib 150 mg tablet twice daily can be safely administered in combination with metronomic carboplatin and paclitaxel in pre-treated relapsed ovarian cancer with 24% complete remission. BRCAm patients had statistically significant longer progression-free survival and overall survival than BRCAwt. TRIAL REGISTRATION NUMBER: NCT01650376.

18.
Cancer Res ; 79(7): 1549-1557, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30723114

RESUMO

The majority of non-small-cell lung cancer (NSCLC) cases are diagnosed at advanced stages, primarily because earlier stages of the disease are either asymptomatic or may be attributed to other causes such as infection or long-term effects from smoking. Therefore, early detection of NSCLC would likely increase response and survival rates due to timely intervention. Here, we utilize a novel approach based on whole genome-derived tiled peptide arrays to identify epitopes associated with autoantibody reactivity in NSCLC as a potential means for early detection. Arrays consisted of 2,781,902 tiled peptides representing 20,193 proteins encoded in the human genome. Analysis of 86 prediagnostic samples and 86 matched normal controls from a high-risk cohort revealed 48 proteins with three or more reactive epitopes in NSCLC samples relative to controls. Independent mass spectrometry analysis identified 40 of the 48 proteins in prediagnostic sera from NSCLC samples, of which, 21 occurred in the immunoglobulin-bound fraction. In addition, 63 and 34 proteins encompassed three or more epitopes that were distinct for squamous cell lung cancer and lung adenocarcinoma, respectively. Collectively, these data show that tiled peptide arrays provide a means to delineate epitopes encoded across the genome that trigger an autoantibody response associated with tumor development. SIGNIFICANCE: This study provides a modality for early diagnosis of NSCLC for precision oncology that can be applied to other cancer types.


Assuntos
Autoanticorpos/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Genoma Humano , Neoplasias Pulmonares/imunologia , Peptídeos/genética , Anexinas/imunologia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Estudos de Casos e Controles , Método Duplo-Cego , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Espectrometria de Massas , Placebos , Medicina de Precisão , Proteína Supressora de Tumor p53/imunologia
19.
J Natl Cancer Inst ; 111(6): 557-567, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30541042

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. METHODS: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. RESULTS: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets. CONCLUSION: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.


Assuntos
Carcinoma Ductal Pancreático/genética , Estudo de Associação Genômica Ampla/métodos , Neoplasias Pancreáticas/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Humanos , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único
20.
Gut ; 68(6): 960-968, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30121626

RESUMO

OBJECTIVE: Cross-sectional data indicate that systemic inflammation is important in oesophageal adenocarcinoma. We conducted a prospective study to assess whether prediagnostic circulating markers of inflammation were associated with oesophageal adenocarcinoma and to what extent they mediated associations of obesity and cigarette smoking with cancer risk. DESIGN: This nested case-control study included 296 oesophageal adenocarcinoma cases and 296 incidence density matched controls from seven prospective cohort studies. We quantitated 69 circulating inflammation markers using Luminex-based multiplex assays. Conditional logistic regression models estimated associations between inflammation markers and oesophageal adenocarcinoma, as well as direct and indirect effects of obesity and smoking on risk of malignancy. RESULTS: Soluble tumour necrosis factor receptor 2 (sTNFR2) (ORsquartile 4 vs 1=2.67, 95% CI 1.52 to 4.68) was significantly associated with oesophageal adenocarcinoma. Additional markers close to the adjusted significance threshold included C reactive protein, serum amyloid A, lipocalin-2, resistin, interleukin (IL) 3, IL17A, soluble IL-6 receptor and soluble vascular endothelial growth factor receptor 3. Adjustment for body mass index, waist circumference or smoking status slightly attenuated biomarker-cancer associations. Mediation analysis indicated that sTNFR2 may account for 33% (p=0.005) of the effect of waist circumference on oesophageal adenocarcinoma risk. Resistin, plasminogen activator inhibitor 1, C reactive protein and serum amyloid A were also identified as potential mediators of obesity-oesophageal adenocarcinoma associations. For smoking status, only plasminogen activator inhibitor 1 was a nominally statistically significant (p<0.05) mediator of cancer risk. CONCLUSION: This prospective study provides evidence of a link between systemic inflammation and oesophageal adenocarcinoma risk. In addition, this study provides the first evidence that indirect effects of excess adiposity and cigarette smoking, via systemic inflammation, increase the risk of oesophageal adenocarcinoma.


Assuntos
Adenocarcinoma/diagnóstico , Biomarcadores Tumorais/sangue , Detecção Precoce de Câncer , Neoplasias Esofágicas/diagnóstico , Mediadores da Inflamação/sangue , Adenocarcinoma/epidemiologia , Adenocarcinoma/metabolismo , Adenocarcinoma/cirurgia , Idoso , Índice de Massa Corporal , Consenso , Estudos Transversais , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/cirurgia , Feminino , Humanos , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Fumar/epidemiologia
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