Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 220
Filtrar
1.
Artigo em Inglês | MEDLINE | ID: mdl-34607083

RESUMO

BACKGROUND & AIMS: Intestinal mucositis, a severe complication of antineoplastic therapeutics, is characterized by mucosal injury and inflammation in the small intestine. Therapies for the prevention and treatment of this disease are needed. We investigated whether 2'-fucosyllactose (2'-FL), an abundant oligosaccharide in human milk, protects intestinal integrity and ameliorates intestinal mucositis. METHODS: A mouse small intestinal epithelial (MSIE) cell line, mouse enteroid cultures, and human gastrointestinal tumor cell lines (AGS and HT29) were co-treated with the chemotherapy agent 5-fluorouracil (5-FU) and 2'-FL. Mice were injected intraperitoneally with 5-FU to induce intestinal mucositis. 2'-FL was administered in the drinking water to mice before (pretreatment) or concurrently with 5-FU injection. Body weight and pathologic changes were analyzed. RESULTS: 2'-FL alleviated 5-FU inhibition of cell growth in MSIE cells, but not in AGS and HT29 cells. The 5-FU-induced apoptosis in MSIE cells and enteroids was suppressed by 2'-FL. Compared with 5-FU treatment alone, 2'-FL pretreatment protected against body weight loss, and ameliorated inflammation scores, proinflammatory cytokine production, shortening of villi, epithelial cell apoptosis, goblet cell loss, and tight junctional complex disruption in the small intestine. 2'-FL concurrent treatment had less of an effect on intestinal mucositis than 2'-FL pretreatment. Interestingly, no effect of 2'-FL was observed on 5-FU-induced S-phase arrest in MSIE, AGS, and HT29 cells. Neither pretreatment nor concurrent treatment with 2'-FL affected 5-FU-induced inhibition of proliferation in MSIE cells. CONCLUSIONS: This study shows a novel direct effect of 2'-FL in protecting small intestinal epithelial cells against apoptosis stimulated by 5-FU, which may contribute to prevention of 5-FU-induced intestinal mucositis.

2.
Int J Cancer ; 2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34664721

RESUMO

Evidence suggests that Helicobacter pylori plays a role in gastric cancer (GC) initiation. However, epidemiologic studies on the specific role of other bacteria in the development of GC are lacking. We conducted a case-control study of 89 cases with gastric intestinal metaplasia (IM) and 89 matched controls who underwent upper gastrointestinal endoscopy at three sites affiliated with NYU Langone Health. We performed shotgun metagenomic sequencing using oral wash samples from 89 case-control pairs and antral mucosal brushing samples from 55 case-control pairs. We examined the associations of relative abundances of bacterial taxa and functional pathways with IM using conditional logistic regression with and without elastic-net penalty. Compared with controls, oral species Peptostreptococcus stomatis, Johnsonella ignava, Neisseria elongata and Neisseria flavescens were enriched in cases (odds ratios [ORs] = 1.29-1.50, P = .004-.01) while Lactobacillus gasseri, Streptococcus mutans, S parasanguinis and S sanguinis were under-represented (ORs = 0.66-0.76, P = .006-.042) in cases. Species J ignava and Filifactor alocis in the gastric microbiota were enriched (ORs = 3.27 and 1.43, P = .005 and .035, respectively), while S mutans, S parasanguinis and S sanguinis were under-represented (ORs = 0.61-0.75, P = .024-.046), in cases compared with controls. The lipopolysaccharide and ubiquinol biosynthesis pathways were more abundant in IM, while the sugar degradation pathways were under-represented in IM. The findings suggest potential roles of certain oral and gastric microbiota, which are correlated with regulation of pathways associated with inflammation, in the development of gastric precancerous lesions.

3.
Br J Cancer ; 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34718358

RESUMO

BACKGROUND: African Americans have the highest pancreatic cancer incidence of any racial/ethnic group in the United States. The oral microbiome was associated with pancreatic cancer risk in a recent study, but no such studies have been conducted in African Americans. Poor oral health, which can be a cause or effect of microbial populations, was associated with an increased risk of pancreatic cancer in a single study of African Americans. METHODS: We prospectively investigated the oral microbiome in relation to pancreatic cancer risk among 122 African-American pancreatic cancer cases and 354 controls. DNA was extracted from oral wash samples for metagenomic shotgun sequencing. Alpha and beta diversity of the microbial profiles were calculated. Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between microbes and pancreatic cancer risk. RESULTS: No associations were observed with alpha or beta diversity, and no individual microbial taxa were differentially abundant between cases and control, after accounting for multiple comparisons. Among never smokers, there were elevated ORs for known oral pathogens: Porphyromonas gingivalis (OR = 1.69, 95% CI: 0.80-3.56), Prevotella intermedia (OR = 1.40, 95% CI: 0.69-2.85), and Tannerella forsythia (OR = 1.36, 95% CI: 0.66-2.77). CONCLUSIONS: Previously reported associations between oral taxa and pancreatic cancer were not present in this African-American population overall.

4.
Int J Cancer ; 2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34664266

RESUMO

Colonization of specific bacteria in the human mouth was reported to be associated with gastric cancer risk. However, previous studies were limited by retrospective study designs and low taxonomic resolutions. We performed a prospective case-control study nested within three cohorts to investigate the relationship between oral microbiome and gastric cancer risk. Shotgun metagenomic sequencing was employed to characterize the microbiome in prediagnostic buccal samples from 165 cases and 323 matched controls. Associations of overall microbial richness and abundance of microbial taxa, gene families and metabolic pathways with gastric cancer risk were evaluated via conditional logistic regression. Analyses were performed within each cohort, and results were combined by meta-analyses. We found that overall microbial richness was associated with decreased gastric cancer risk, with an odds ratio (OR) per standard deviation (SD) increase in Simpson's reciprocal index of 0.77 (95% confidence interval [CI] = 0.61-0.99). Nine taxa, 38 gene families and six pathways also showed associations with gastric cancer risk at P < .05. Neisseria mucosa and Prevotella pleuritidis were enriched, while Mycoplasma orale and Eubacterium yurii were depleted among cases with ORs and 95% CIs per SD increase in centered log-ratio transformed taxa abundance of 1.31 (1.03-1.67), 1.26 (1.00-1.57), 0.74 (0.59-0.94) and 0.80 (0.65-0.98), respectively. The top two gene families (P = 3.75 × 10-4 and 3.91 × 10-4 ) and pathways (P = 1.75 × 10-3 and 1.53 × 10-3 ) associated with gastric cancer were related to the decreased risk and are involved in hexitol metabolism. Our study supports the hypothesis that oral microbiota may play a role in gastric cancer etiology.

5.
Microorganisms ; 9(10)2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34683439

RESUMO

Non-alcoholic fatty liver disease (NAFLD) has been linked to altered gut microbiome; however, evidence from large population-based studies is limited. We compared gut microbiome profiles of 188 male and 233 female NAFLD cases with 571 male and 567 female controls from two longitudinal studies of urban Chinese adults. History of NAFLD was assessed during surveys administered in 2004-2017. Microbiota were assessed using 16S rRNA sequencing of stool samples collected in 2015-2018. Associations of NAFLD with microbiome diversity and composition were evaluated by generalized linear or logistic regression models. Compared with controls, male cases had lower microbial α-diversity, higher abundance of genera Dialister and Streptococcus and Bifidobacterium species, lower abundance of genus Phascolarctobacterium, and lower prevalence of taxa including order RF39 (all p < 0.05). In contrast, female cases had higher α-diversity, higher abundance of genus Butyricimonas and a family of order Clostridiales, lower abundance of Dialister and Bifidobacterium species, and higher prevalence of RF39. Significant NAFLD-sex interactions were found for α-diversity and above taxa (all false discovery rate < 0.1). In conclusion, we observed sex-specific gut microbiome features related to history of NAFLD. Further studies are needed to validate our findings and evaluate the health effects of NAFLD-related gut microbiota.

6.
Cancer Commun (Lond) ; 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34520132

RESUMO

BACKGROUND: DNA methylation and gene expression are known to play important roles in the etiology of human diseases such as prostate cancer (PCa). However, it has not yet been possible to incorporate information of DNA methylation and gene expression into polygenic risk scores (PRSs). Here, we aimed to develop and validate an improved PRS for PCa risk by incorporating genetically predicted gene expression and DNA methylation, and other genomic information using an integrative method. METHODS: Using data from the PRACTICAL consortium, we derived multiple sets of genetic scores, including those based on available single-nucleotide polymorphisms through widely used methods of pruning and thresholding, LDpred, LDpred-funt, AnnoPred, and EBPRS, as well as PRS constructed using the genetically predicted gene expression and DNA methylation through a revised pruning and thresholding strategy. In the tuning step, using the UK Biobank data (1458 prevalent cases and 1467 controls), we selected PRSs with the best performance. Using an independent set of data from the UK Biobank, we developed an integrative PRS combining information from individual scores. Furthermore, in the testing step, we tested the performance of the integrative PRS in another independent set of UK Biobank data of incident cases and controls. RESULTS: Our constructed PRS had improved performance (C statistics: 76.1%) over PRSs constructed by individual benchmark methods (from 69.6% to 74.7%). Furthermore, our new PRS had much higher risk assessment power than family history. The overall net reclassification improvement was 69.0% by adding PRS to the baseline model compared with 12.5% by adding family history. CONCLUSIONS: We developed and validated a new PRS which may improve the utility in predicting the risk of developing PCa. Our innovative method can also be applied to other human diseases to improve risk prediction across multiple outcomes.

7.
Cancer Epidemiol Biomarkers Prev ; 30(11): 2079-2087, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34497089

RESUMO

BACKGROUND: The role of methylation in pancreatic cancer risk remains unclear. We integrated genome and methylome data to identify CpG sites (CpG) with the genetically predicted methylation to be associated with pancreatic cancer risk. We also studied gene expression to understand the identified associations. METHODS: Using genetic data and white blood cell methylation data from 1,595 subjects of European descent, we built genetic models to predict DNA methylation levels. After internal and external validation, we applied prediction models with satisfactory performance to the genetic data of 8,280 pancreatic cancer cases and 6,728 controls of European ancestry to investigate the associations of predicted methylation with pancreatic cancer risk. For associated CpGs, we compared their measured levels in pancreatic tumor versus benign tissue. RESULTS: We identified 45 CpGs at nine loci showing an association with pancreatic cancer risk, including 15 CpGs showing an association independent from identified risk variants. We observed significant correlations between predicted methylation of 16 of the 45 CpGs and predicted expression of eight adjacent genes, of which six genes showed associations with pancreatic cancer risk. Of the 45 CpGs, we were able to compare measured methylation of 16 in pancreatic tumor versus benign pancreatic tissue. Of them, six showed differentiated methylation. CONCLUSIONS: We identified methylation biomarker candidates associated with pancreatic cancer using genetic instruments and added additional insights into the role of methylation in regulating gene expression in pancreatic cancer development. IMPACT: A comprehensive study using genetic instruments identifies 45 CpG sites at nine genomic loci for pancreatic cancer risk.

8.
Hum Genet ; 140(10): 1449-1457, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34487234

RESUMO

Single germline nucleotide pathogenic variants have been identified in 12 breast cancer predisposition genes, but structural deletions in these genes remain poorly characterized. We conducted in-depth whole genome sequencing (WGS) in genomic DNA samples obtained from 1340 invasive breast cancer cases and 675 controls of African ancestry. We identified 25 deletions in the intragenic regions of ten established breast cancer predisposition genes based on a consensus call from six state-of-the-art SV callers. Overall, no significant case-control difference was found in the frequency of these deletions. However, 1.0% of cases and 0.3% of controls carried any of the eight putative protein-truncating rare deletions located in BRCA1, BRCA2, CDH1, TP53, NF1, RAD51D, RAD51C and CHEK2, resulting in an odds ratio (OR) of 3.29 (95% CI 0.74-30.16). We also identified a low-frequency deletion in NF1 associated with breast cancer risk (OR 1.93, 95% CI 1.14-3.42). In addition, we detected 56 deletions, including six putative protein-truncating deletions, in suspected breast predisposition genes. This is the first large study to systematically search for structural deletions in breast cancer predisposition genes. Many of the deletions, particularly those resulting in protein truncations, are likely to be pathogenic. Results from this study, if confirmed in future large-scale studies, could have significant implications for genetic testing for this common cancer.


Assuntos
Afro-Americanos/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Deleção de Genes , Predisposição Genética para Doença , Sequenciamento Completo do Genoma , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Estados Unidos
9.
Cancer Causes Control ; 32(12): 1423-1432, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34432217

RESUMO

PURPOSE: Oral microbiome plays an important role in oral health and systemic diseases, including cancer. We aimed to prospectively investigate the association of oral microbiome with lung cancer risk. METHODS: We analyzed 156 incident lung cancer cases (73 European Americans and 83 African Americans) and 156 individually matched controls nested within the Southern Community Cohort Study. Oral microbiota were assessed using 16S rRNA gene sequencing in pre-diagnostic mouth rinse samples. Paired t test and the permutational multivariate analysis of variance test were used to evaluate lung cancer risk association with alpha diversity or beta diversity, respectively. Conditional logistic regression models were used to evaluate the association of individual bacterial abundance or prevalence with lung cancer risk. RESULTS: No significant differences were observed for alpha or beta diversity between lung cancer cases and controls. Abundance of families Lachnospiraceae_[XIV], Peptostreptococcaceae_[XI], and Erysipelotrichaceae and species Parvimonas micra was associated with decreased lung cancer risk, with odds ratios (ORs) and 95% confidence intervals (CIs) of 0.76 (0.59-0.98), 0.80 (0.66-0.97), 0.81 (0.67-0.99), and 0.83 (0.71-0.98), respectively (all p < 0.05). Prevalence of five pre-defined oral pathogens were not significantly associated with overall lung cancer risk. Prevalence of genus Bacteroidetes_[G-5] and species Alloprevotella sp._oral_taxon_912, Capnocytophaga sputigena, Lactococcus lactis, Peptoniphilaceae_[G-1] sp._oral_taxon_113, Leptotrichia sp._oral_taxon_225, and Fretibacterium fastidiosum was associated with decreased lung cancer risk, with ORs and 95% CIs of 0.55 (0.30-1.00), 0.36 (0.17-0.73), 0.53 (0.31-0.92), 0.43 (0.21-0.88), 0.43 (0.19-0.94), 0.57 (0.34-0.99), and 0.54 (0.31-0.94), respectively (all p < 0.05). Species L. sp._oral_taxon_225 was significantly associated with decreased lung cancer risk in African Americans (OR [95% CIs] 0.28 [0.12-0.66]; p = 0.00012). CONCLUSION: Results from this study suggest that oral microbiota may play a role in the development of lung cancer.


Assuntos
Neoplasias Pulmonares , Microbiota , Bactérias , Capnocytophaga , Estudos de Coortes , Firmicutes , Humanos , Neoplasias Pulmonares/epidemiologia , Pobreza , RNA Ribossômico 16S/genética
10.
J Nutr ; 151(8): 2399-2408, 2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34114016

RESUMO

BACKGROUND: Legumes, important components of a healthy diet, may exert their health benefits through the influence of the gut microbiome. However, this hypothesis has not been well investigated. OBJECTIVE: This study aimed to examine the associations between long-term legume consumption and the gut microbiome among elderly Chinese. METHODS: The gut microbiome was profiled by 16S ribosomal RNA sequencing in 2302 Chinese adults enrolled in 2 large cohort studies, the Shanghai Women's Health Study and Shanghai Men's Health Study. Legume consumption, including peanuts, soy foods, and other beans, was assessed by food-frequency questionnaires prior to the stool collection. The associations of legume consumption with microbiome diversity and taxa abundance were evaluated by linear or negative binomial hurdle models, adjusting for sociodemographics, lifestyle factors, and BMI. False discovery rate (FDR)-corrected P values (PFDR) < 0.1 were considered significant. RESULTS: Respectively, 52% and 48% of study participants were male and female. The mean age at stool collection was 68.03 y for females and 70.28 y for males. Total legume consumption was not associated with gut microbiome ɑ-diversity; however, male peanut consumers had a higher Chao1 index (ß = 22.52, P = 0.01), whereas peanut consumption was associated with decreased Shannon (ß = -0.03, P = 0.02) and Simpson (ß = -0.002, P = 0.04) indexes among females. In female and male combined analyses, total legume consumption was associated with increased Enterobacteriales (ß = 0.30, PFDR = 0.06). Within this order, an unclassified genus in the family Enterobacteriaceae was positively associated with total legume (ß = 0.46, PFDR = 0.03) and peanut (ß = 0.59, PFDR = 0.01) consumption. Stratified analyses showed significant associations were primarily confined to females and participants without metabolic conditions. CONCLUSIONS: Legume consumption was associated with gut microbiome diversity and abundance of some bacteria in elderly Chinese. Associations were significant only among 1 sex group. Further research, including large-scale prospective studies and feeding trials, is needed to fully understand the role of the gut microbiome in legume-health associations.

11.
Curr Dev Nutr ; 5(4): nzab026, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33937616

RESUMO

Background: Diet is known to affect human gut microbiome composition; yet, how diet affects gut microbiome functionality remains unclear. Objective: We compared the diversity and abundance/presence of fecal microbiome metabolic pathways among individuals according to their long-term diet quality. Methods: In 2 longitudinal cohorts, we assessed participants' usual diets via repeated surveys during 1996-2011 and collected a stool sample in 2015-2018. Participants who maintained a healthy or unhealthy diet (i.e., stayed in the highest or lowest quintile of a healthy diet score throughout follow-up) were selected. Participants were excluded if they reported a history of cancer, cardiovascular disease, diabetes, or hypertension; had diarrhea or constipation in the last 7 d; or used antibiotics in the last 6 mo before stool collection. Functional profiling of shotgun metagenomics was performed using HUMAnN2. Associations of dietary variables and 420 microbial metabolic pathways were evaluated via multivariable-adjusted linear or logistic regression models. Results: We included 144 adults (mean age = 64 y; 55% female); 66 had an unhealthy diet and 78 maintained a healthy diet. The healthy diet group had higher Shannon α-diversity indexes of microbial gene families and metabolic pathways (both P < 0.02), whereas ß-diversity, as evaluated by Bray-Curtis distance, did not differ between groups (both P > 0.50). At P < 0.01 [false discovery rate (FDR) <0.15], the healthy diet group showed enriched pathways for vitamin and carrier biosynthesis (e.g., tetrahydrofolate, acetyl-CoA, and l-methionine) and tricarboxylic acid (TCA) cycle, and increased degradation (or reduced biosynthesis) of certain sugars [e.g., cytidine monophosphate (CMP)-legionaminate, deoxythymidine diphosphate (dTDP)-l-rhamnose, and sucrose], nucleotides, 4-aminobutanoate, methylglyoxal, sulfate, and aromatic compounds (e.g., catechol and toluene). Meanwhile, several food groups were associated with the CMP-legionaminate biosynthesis pathway at FDR <0.05. Conclusions: In a small longitudinal study of generally healthy, older Chinese adults, we found long-term healthy eating was associated with increased α-diversity of microbial gene families and metabolic pathways and altered symbiotic functions relevant to human nutrition and health.

12.
Clin Transl Gastroenterol ; 12(5): e00344, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33955373

RESUMO

INTRODUCTION: Colorectal cancer (CRC) screening reduces CRC incidence and mortality. However, it is unclear whether the reduction in CRC risk may differ by genetic susceptibility. METHODS: We evaluated this question in a cohort of 304,740 participants of European descent aged 50 years and older. Genetic susceptibility was measured using a polygenic risk score (PRS) constructed with risk variants identified in genomewide association studies. Cox models were used to estimate hazard ratios and 95% confidence intervals of CRC risk. RESULTS: Over a median follow-up of 7.0 years, 2,261 incident CRC cases and 528 CRC deaths were identified. CRC screening was associated with a significantly reduced CRC incidence among individuals with a high (hazard ratio, 0.80; 95% confidence interval, 0.71-0.92) and intermediate PRS (0.84, 0.71-0.98) but not among those with a low PRS (1.03, 0.86-1.25; Pinteraction, 0.005). A similar but more evident difference was observed for mortality (Pinteraction, 0.046), with more than 30% reduced mortality observed in the high PRS group (0.69, 0.52-0.91). Among the younger group (age 50-60 years), CRC screenings were associated with a slightly (but nonsignificantly) elevated incidence and mortality in the low PRS group but a reduced risk in the high PRS group (Pinteraction, 0.043 [incidence]; 0.092 [mortality]). No significant interaction was observed in the older group (age > 60 years). DISCUSSION: Individuals with a higher genetic risk benefited more substantially from CRC screenings than those with a lower risk. Our findings suggest that PRS may be used to develop personalized CRC screening to maximize its effect on CRC prevention.


Assuntos
Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/mortalidade , Detecção Precoce de Câncer , Programas de Rastreamento , Neoplasias Colorretais/genética , Neoplasias Colorretais/prevenção & controle , Feminino , Seguimentos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Medição de Risco , Reino Unido/epidemiologia
13.
Cancers (Basel) ; 13(9)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33925895

RESUMO

Endometrial cancer (EC) is the leading female reproductive tract malignancy in developed countries. Currently, genome-wide association studies (GWAS) have identified 17 risk loci for EC. To identify novel EC-associated proteins, we used previously reported protein quantitative trait loci for 1434 plasma proteins as instruments to evaluate associations between genetically predicted circulating protein concentrations and EC risk. We studied 12,906 cases and 108,979 controls of European descent included in the Endometrial Cancer Association Consortium, the Epidemiology of Endometrial Cancer Consortium, and the UK Biobank. We observed associations between genetically predicted concentrations of nine proteins and EC risk at a false discovery rate of <0.05 (p-values range from 1.14 × 10-10 to 3.04 × 10-4). Except for vascular cell adhesion protein 1, all other identified proteins were independent from known EC risk variants identified in EC GWAS. The respective odds ratios (95% confidence intervals) per one standard deviation increase in genetically predicted circulating protein concentrations were 1.21 (1.13, 1.30) for DNA repair protein RAD51 homolog 4, 1.27 (1.14, 1.42) for desmoglein-2, 1.14 (1.07, 1.22) for MHC class I polypeptide-related sequence B, 1.05 (1.02, 1.08) for histo-blood group ABO system transferase, 0.77 (0.68, 0.89) for intestinal-type alkaline phosphatase, 0.82 (0.74, 0.91) for carbohydrate sulfotransferase 15, 1.07 (1.03, 1.11) for D-glucuronyl C5-epimerase, and 1.07 (1.03, 1.10) for CD209 antigen. In conclusion, we identified nine potential EC-associated proteins. If validated by additional studies, our findings may contribute to understanding the pathogenesis of endometrial tumor development and identifying women at high risk of EC along with other EC risk factors and biomarkers.

14.
Cancers (Basel) ; 13(9)2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33922500

RESUMO

We previously identified a locus at 21q22.3, tagged by the single nucleotide polymorphism (SNP) rs35418111, being associated with breast cancer risk at a genome-wide significance level; however, the underlying causal functional variants and gene(s) responsible for this association are unknown. We performed functional genomic analyses to identify potential functional variants and target genes that may mediate this association. Functional annotation for SNPs in high linkage disequilibrium (LD, r2 > 0.8) with rs35418111 in Asians showed evidence of promoter and/or enhancer activities, including rs35418111, rs2078203, rs8134832, rs57385578, and rs8126917. These five variants were assessed for interactions with nuclear proteins by electrophoretic mobility shift assays. Our results showed that the risk alleles for rs2078203 and rs35418111 altered DNA-protein interaction patterns. Cis-expression quantitative loci (cis-eQTL) analysis, using data from the Genotype-Tissue Expression database (GTEx) European-ancestry female normal breast tissue, indicated that the risk allele of rs35418111 was associated with a decreased expression of the YBEY gene, a relatively uncharacterized endoribonuclease in humans. We investigated the biological effects of YBEY on breast cancer cell lines by transient knock-down of YBEY expression in MCF-7, T47D, and MDA-MB-231 cell lines. Knockdown of YBEY mRNA in breast cancer cell lines consistently decreased cell proliferation, colony formation, and migration/invasion, regardless of estrogen receptor status. We performed RNA sequencing in MDA-MB-231 cells transfected with siRNA targeting YBEY and subsequent gene set enrichment analysis to identify gene networks associated with YBEY knockdown. These data indicated YBEY was involved in networks associated with inflammation and metabolism. Finally, we showed trends in YBEY expression patterns in breast tissues from The Cancer Genome Atlas (TCGA); early-stage breast cancers had elevated YBEY expression compared with normal tissue, but significantly decreased expression in late-stage disease. Our study provides evidence of a significant role for the human YBEY gene in breast cancer pathogenesis and the association between the rs35418111/21q22.3 locus and breast cancer risk, which may be mediated through functional SNPs, rs35418111 and rs2078203, that regulate expression of YBEY.

15.
Genet Epidemiol ; 45(5): 471-484, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33739539

RESUMO

Previous genome-wide association studies (GWASs) have been largely focused on European (EUR) populations. However, polygenic risk scores (PRSs) derived from EUR have been shown to perform worse in non-EURs compared with EURs. In this study, we aim to improve PRS prediction in East Asians (EASs). We introduce a rescaled meta-analysis framework to combine both EUR (N = 122,175) and EAS (N = 30,801) GWAS summary statistics. To improve PRS prediction in EASs, we use a scaling factor to up-weight the EAS data, such that the resulting effect size estimates are more relevant to EASs. We then derive PRSs for EAS from the rescaled meta-analysis results of EAS and EUR data. Evaluated in an independent EAS validation data set, this approach increases the prediction liability-adjusted Nagelkerke's pseudo R2 by 40%, 41%, and 5%, respectively, compared with PRSs derived from an EAS GWAS only, EUR GWAS only, and conventional fixed-effects meta-analysis of EAS and EUR data. The PRS derived from the rescaled meta-analysis approach achieved an area under the receiver operating characteristic curve (AUC) of 0.6059, higher than AUC = 0.5782, 0.5809, 0.6008 for EAS, EUR, and conventional meta-analysis of EAS and EUR. We further compare PRSs constructed by single-nucleotide polymorphisms that have different linkage disequilibrium (LD) scores and minor allele frequencies (MAFs) between EUR and EAS, and observe that lower LD scores or MAF in EAS correspond to poorer PRS performance (AUC = 0.5677, 0.5530, respectively) than higher LD scores or MAF (AUC = 0.589, 0.5993, respectively). We finally build a PRS stratified by LD score differences in EUR and EAS using rescaled meta-analysis, and obtain an AUC of 0.6096, with improvement over other strategies investigated.


Assuntos
Neoplasias da Mama , Estudo de Associação Genômica Ampla , Grupo com Ancestrais do Continente Asiático/genética , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Humanos , Herança Multifatorial , Polimorfismo de Nucleotídeo Único
16.
Am J Clin Nutr ; 113(3): 684-694, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33471054

RESUMO

BACKGROUND: Few population-based studies have evaluated the influence of long-term diet on the gut microbiome, and data among Asian populations are lacking. OBJECTIVE: We examined the association of long-term diet quality, comprising 8 food groups (fruit, vegetables, dairy, fish/seafood, nuts/legumes, refined grains, red meat, and processed meat), with gut microbiome among Chinese adults. METHODS: Included were 1920 men and women, enrolled in 2 prospective cohorts (baseline 1996-2006), who remained free of cardiovascular diseases, diabetes, and cancer at stool collection (2015-2018) and had no diarrhea or antibiotic use in the last 7 d before stool collection. Microbiome was profiled by 16S rRNA sequencing. Long-term diet was assessed by repeated surveys at baseline and follow-ups (1996-2011), with intervals of 5.2 to 20.5 y between dietary surveys and stool collection. Associations of dietary variables with microbiome diversity and composition were evaluated by linear or negative binomial hurdle models, adjusting for potential confounders. False discovery rate (FDR) <0.1 was considered significant. RESULTS: The mean ± SD age at stool collection was 68 ± 1.5 y. Diet quality was positively associated with microbiome α-diversity (P = 0.03) and abundance of Firmicutes, Actinobacteria, Tenericutes, and genera/species within these phyla, including Coprococcus, Faecalibacterium/Faecalibacterium prausnitzii, Bifidobacterium / Bifidobacterium adolescentis, and order RF39 (all FDRs <0.1). Significant associations were also observed for intakes of dairy, fish/seafood, nuts/legumes, refined grains, and processed meat, including a positive association of dairy with Bifidobacterium and inverse associations of processed meat with Roseburia /Roseburia faecis. Most associations were similar, with or without adjustment for BMI and hypertension status or excluding participants with antibiotic use in the past 6 mo. CONCLUSION: Among apparently healthy Chinese adults, long-term diet quality is positively associated with fecal microbiome diversity and abundance of fiber-fermenting bacteria, although magnitudes are generally small. Future studies are needed to examine if these bacteria may mediate or modify diet-disease relations.


Assuntos
Grupo com Ancestrais do Continente Asiático , Bactérias/classificação , Dieta/normas , Microbioma Gastrointestinal , População Urbana , Adulto , Idoso , Bactérias/genética , Estudos de Coortes , Fezes/microbiologia , Comportamento Alimentar , Feminino , Humanos , Masculino , RNA Bacteriano/genética , RNA Ribossômico 16S/genética
17.
Cancer Res Treat ; 53(3): 754-762, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33421985

RESUMO

PURPOSE: Excessive alcohol consumption has been linked to an increased risk of colorectal cancer (CRC). We evaluated the association between alcohol-related genetic variants and CRC risk. MATERIALS AND METHODS: The study cohort consisted of 5,435 CRC cases and 3,553 population-based cancer-free controls. Genotype data were generated from germline DNA using the Infinium OncoArray-500K BeadChip in 2,535 cases and 2,287 controls and the Infinium Multi-Ethnic Global BeadChip in 2,900 cases and 1,266 controls. The associations between aldehyde dehydrogenase 2 (ALDH2) rs671 and alcohol dehydrogenase 1B (ADH1B) rs1229984 polymorphisms and CRC risk were assessed using multivariate logistic regression analyses. RESULTS: Compared with the major homozygous ALDH2 genotype (GG), heterozygous or minor homozygous ALDH2 genotype (GA or AA, related to a low alcohol consumption) was significantly associated with a reduced risk for CRC in men (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.68 to 0.90), but not in women (OR, 0.70; 95% CI, 0.47 to 1.05). A stronger association was found among regular drinkers (OR, 0.58; 95% CI, 0.47 to 0.71 in men and OR, 0.33; 95% CI, 0.18 to 0.58 in women). No association of CRC risk with ADH1B rs1229984 genotype was found. The association between alcohol-related combined genotypes and risk of CRC was significant (p for linear=0.001). The combined genotype with the highest genetically predicted alcohol consumption (ALDH2 rs671 GG and ADH1B rs1229984 AG/GG) was associated with a high risk for CRC (OR, 1.35; 95% CI, 1.11 to 1.63). CONCLUSION: Our study provides strong evidence for a possible causal association between alcohol consumption and CRC risk.

18.
Hum Mol Genet ; 30(5): 321-330, 2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33481017

RESUMO

Most genetic variants for colorectal cancer (CRC) identified in genome-wide association studies (GWAS) are located in intergenic regions, implying pathogenic dysregulations of gene expression. However, comprehensive assessments of target genes in CRC remain to be explored. We conducted a multi-omics analysis using transcriptome and/or DNA methylation data from the Genotype-Tissue Expression, The Cancer Genome Atlas and the Colonomics projects. We identified 116 putative target genes for 45 GWAS-identified variants. Using summary-data-based Mendelian randomization approach (SMR), we demonstrated that the CRC susceptibility for 29 out of the 45 CRC variants may be mediated by cis-effects on gene regulation. At a cutoff of the Bonferroni-corrected PSMR < 0.05, we determined 66 putative susceptibility genes, including 39 genes that have not been previously reported. We further performed in vitro assays for two selected genes, DIP2B and SFMBT1, and provide functional evidence that they play a vital role in colorectal carcinogenesis via disrupting cell behavior, including migration, invasion and epithelial-mesenchymal transition. Our study reveals a large number of putative novel susceptibility genes and provides additional insight into the underlying mechanisms for CRC genetic risk loci.


Assuntos
Carcinogênese/genética , Neoplasias Colorretais/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Proteínas do Tecido Nervoso/genética , Proteínas Repressoras/genética , Transcriptoma , Linhagem Celular Tumoral , Proliferação de Células , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Genoma , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco
19.
Gastroenterology ; 160(4): 1164-1178.e6, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33058866

RESUMO

BACKGROUND AND AIMS: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes. METHODS: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted. RESULTS: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10-6, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis. CONCLUSIONS: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Modelos Genéticos , Alelos , Carcinogênese/genética , Estudos de Casos e Controles , Estudos de Coortes , Neoplasias Colorretais/epidemiologia , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , RNA-Seq , Fatores de Risco , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Thorax ; 76(3): 256-263, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33318237

RESUMO

OBJECTIVE: To prospectively investigate whether diversity in oral microbiota is associated with risk of lung cancer among never-smokers. DESIGN AND SETTING: A nested case-control study within two prospective cohort studies, the Shanghai Women's Health Study (n=74 941) and the Shanghai Men's Health Study (n=61 480). PARTICIPANTS: Lifetime never-smokers who had no cancer at baseline. Cases were subjects who were diagnosed with incident lung cancer (n=114) and were matched 1:1 with controls on sex, age (≤2 years), date (≤30 days) and time (morning/afternoon) of sample collection, antibiotic use during the week before sample collection (yes/no) and menopausal status (for women). MAIN OUTCOMES AND MEASURES: Metagenomic shotgun sequencing was used to measure the community structure and abundance of the oral microbiome in pre-diagnostic oral rinse samples of each case and control. Multivariable logistic regression models were used to estimate the association of lung cancer risk with alpha diversity metrics and relative abundance of taxa. The Microbiome Regression-Based Kernel Association Test (MiRKAT) evaluated the association between risk and the microbiome beta diversity. RESULTS: Subjects with lower microbiota alpha diversity had an increased risk of lung cancer compared with those with higher microbial alpha diversity (Shannon: ptrend=0.05; Simpson: ptrend=0.04; Observed Species: ptrend=0.64). No case-control differences were apparent for beta diversity (pMiRKAT=0.30). After accounting for multiple comparisons, a greater abundance of Spirochaetia (ORlow 1.00 (reference), ORmedium 0.61 (95% CI 0.32 to 1.18), ORhigh 0.42 (95% CI 0.21 to 0.85)) and Bacteroidetes (ORlow 1.00 (reference), ORmedium 0.66 (95% CI 0.35 to 1.25), ORhigh 0.31 (95% CI 0.15 to 0.64)) was associated with a decreased risk of lung cancer, while a greater abundance of the Bacilli class (ORlow 1.00 (reference), ORmedium 1.49 (95% CI 0.73 to 3.08), ORhigh 2.40 (95% CI 1.18 to 4.87)) and Lactobacillales order (ORlow 1.00 (reference), ORmedium 2.15 (95% CI 1.03 to 4.47), ORhigh 3.26 (95% CI 1.58 to 6.70)) was associated with an increased risk of lung cancer. CONCLUSIONS: Our prospective study of never-smokers suggests that lower alpha diversity was associated with a greater risk of lung cancer and the abundance of certain specific taxa was associated with altered risk, providing further insight into the aetiology of lung cancer in the absence of active tobacco smoking.


Assuntos
Neoplasias Pulmonares/epidemiologia , Microbiota , Mucosa Bucal/microbiologia , Estudos de Casos e Controles , China/epidemiologia , Feminino , Humanos , Incidência , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Fumantes
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...