RESUMO
BACKGROUND: To understand the shared genetic basis between colorectal cancer (CRC) and other cancers and identify potential pleiotropic loci for compensating the missing genetic heritability of CRC. METHODS: We conducted a systematic genome-wide pleiotropy scan to appraise associations between cancer-related genetic variants and CRC risk among European populations. Single nucleotide polymorphism (SNP)-set analysis was performed using data from the UK Biobank and the Study of Colorectal Cancer in Scotland (10 039 CRC cases and 30 277 controls) to evaluate the overlapped genetic regions for susceptibility of CRC and other cancers. The variant-level pleiotropic associations between CRC and other cancers were examined by CRC genome-wide association study meta-analysis and the pleiotropic analysis under composite null hypothesis (PLACO) pleiotropy test. Gene-based, co-expression and pathway enrichment analyses were performed to explore potential shared biological pathways. The interaction between novel genetic variants and common environmental factors was further examined for their effects on CRC. RESULTS: Genome-wide pleiotropic analysis identified three novel SNPs (rs2230469, rs9277378 and rs143190905) and three mapped genes (PIP4K2A, HLA-DPB1 and RTEL1) to be associated with CRC. These genetic variants were significant expressions quantitative trait loci in colon tissue, influencing the expression of their mapped genes. Significant interactions of PIP4K2A and HLA-DPB1 with environmental factors, including smoking and alcohol drinking, were observed. All mapped genes and their co-expressed genes were significantly enriched in pathways involved in carcinogenesis. CONCLUSION: Our findings provide an important insight into the shared genetic basis between CRC and other cancers. We revealed several novel CRC susceptibility loci to help understand the genetic architecture of CRC.
Assuntos
Neoplasias Colorretais , Estudo de Associação Genômica Ampla , Humanos , Neoplasias Colorretais/genética , Risco , Loci Gênicos , Consumo de Bebidas Alcoólicas , Locos de Características Quantitativas/genética , Polimorfismo de Nucleotídeo Único/genética , Predisposição Genética para Doença , Fosfotransferases (Aceptor do Grupo Álcool)RESUMO
Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Y/genética , Predisposição Genética para Doença/genética , Instabilidade Genômica/genética , Leucócitos/patologia , Mosaicismo , Adulto , Idoso , Biologia Computacional , Bases de Dados Genéticas , Feminino , Marcadores Genéticos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Reino UnidoRESUMO
BACKGROUND: To investigate the association between circulating 25-hydroxyvitamin D (25-OHD) and colorectal cancer (CRC) survival outcomes. METHODS: We conducted analyses among the Study of Colorectal Cancer in Scotland (SOCCS) and the UK Biobank (UKBB). Both cancer-specific survival (CSS) and overall survival (OS) outcomes were examined. The 25-OHD levels were categorised into three groups, and multi-variable Cox-proportional hazard models were applied to estimate hazard ratios (HRs). We performed individual-level Mendelian randomisation (MR) through the generated polygenic risk scores (PRS) of 25-OHD and summary-level MR using the inverse-variance weighted (IVW) method. RESULTS: We observed significantly poorer CSS (HR = 0.65,95%CI = 0.55-0.76,P = 1.03 × 10-7) and OS (HR = 0.66,95%CI = 0.58-0.75,P = 8.15 × 10-11) in patients with the lowest compared to those with the highest 25-OHD after adjusting for covariates. These associations remained across patients with varied tumour sites and stages. However, we found no significant association between 25-OHD PRS and either CSS (HR = 0.98,95%CI = 0.80-1.19,P = 0.83) or OS (HR = 1.07,95%CI = 0.91-1.25,P = 0.42). Furthermore, we found no evidence for causal effects by conducting summary-level MR analysis for either CSS (IVW:HR = 1.04,95%CI = 0.85-1.28,P = 0.70) or OS (IVW:HR = 1.10,95%CI = 0.93-1.31,P = 0.25). CONCLUSION: This study supports the observed association between lower circulating 25-OHD and poorer survival outcomes for CRC patients. Whilst the genotype-specific association between better outcomes and higher 25-OHD is intriguing, we found no support for causality using MR approaches.
Assuntos
Neoplasias Colorretais , Análise da Randomização Mendeliana , Vitamina D , Vitamina D/análogos & derivados , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Vitamina D/sangue , Masculino , Feminino , Estudos Prospectivos , Pessoa de Meia-Idade , Idoso , Escócia/epidemiologia , Modelos de Riscos Proporcionais , AdultoRESUMO
Aberrant smoking-related DNA methylation has been widely investigated as a carcinogenesis mechanism, but whether the cross-cancer epigenetic pathways exist remains unclear. We conducted two-sample Mendelian randomization (MR) analyses respectively on smoking behaviors (age of smoking initiation, smoking initiation, smoking cessation, and lifetime smoking index [LSI]) and smoking-related DNA methylation to investigate their effect on 15 site-specific cancers, based on a genome-wide association study (GWAS) of 1.2 million European individuals and an epigenome-WAS (EWAS) of 5907 blood samples of Europeans for smoking and 15 GWASs of European ancestry for multiple site-specific cancers. Significantly identified CpG sites were further used for colocalization analysis, and those with cross-cancer effect were validated by overlapping with tissue-specific eQTLs. In the genomic MR, smoking measurements of smoking initiation, smoking cessation and LSI were suggested to be casually associated with risk of seven types of site-specific cancers, among which cancers at lung, cervix and colorectum were provided with strong evidence. In the epigenetic MR, methylation at 75 CpG sites were reported to be significantly associated with increased risks of multiple cancers. Eight out of 75 CpG sites were observed with cross-cancer effect, among which cg06639488 (EFNA1), cg12101586 (CYP1A1) and cg14142171 (HLA-L) were validated by eQTLs at specific cancer sites, and cg07932199 (ATXN2) had strong evidence to be associated with cancers of lung (coefficient, 0.65, 95% confidence interval [CI], 0.31-1.00), colorectum (0.90 [0.61, 1.18]), breast (0.31 [0.20, 0.43]) and endometrium (0.98 [0.68, 1.27]). These findings highlight the potential practices targeting DNA methylation-involved cross-cancer pathways.
Assuntos
Metilação de DNA , Neoplasias , Feminino , Humanos , Fumar/efeitos adversos , Fumar/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Neoplasias/epidemiologia , Neoplasias/genética , Ilhas de CpG/genéticaRESUMO
BACKGROUND: Tobacco smoking is suggested as a risk factor for colorectal cancer (CRC), but the complex relationship and the potential pathway are not fully understood. METHODS: We performed two-sample Mendelian randomisation (MR) analyses with genetic instruments for smoking behaviours and related DNA methylation in blood and summary-level GWAS data of colorectal cancer to disentangle the relationship. Colocalization analyses and prospective gene-environment interaction analyses were also conducted as replication. RESULTS: Convincing evidence was identified for the pathogenic effect of smoking initiation on CRC risk and suggestive evidence was observed for the protective effect of smoking cessation in the univariable MR analyses. Multivariable MR analysis revealed that these associations were independent of other smoking phenotypes and alcohol drinking. Genetically predicted methylation at CpG site cg17823346 [ZMIZ1] were identified to decrease CRC risk; while genetically predicted methylation at cg02149899 would increase CRC risk. Colocalization and gene-environment interaction analyses added further evidence to the relationship between epigenetic modification at cg17823346 [ZMIZ1] as well as cg02149899 and CRC risk. DISCUSSION: Our study confirms the significant association between tobacco smoking, DNA methylation and CRC risk and yields a novel insight into the pathogenic effect of tobacco smoking on CRC risk.
Assuntos
Neoplasias Colorretais , Fumar , Humanos , Fumar/efeitos adversos , Metilação de DNA , Estudos Prospectivos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Fumar Tabaco , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo ÚnicoRESUMO
INTRODUCTION: The joint associations across genetic risk, modifiable lifestyle factors, and inflammatory bowel disease (IBD) remains unclear. METHODS: Genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) was estimated by polygenic risk scores and further categorized into high, intermediate, and low genetic risk categories. Weighted healthy lifestyle scores were constructed based on 5 common lifestyle factors and categorized into favorable (4 or 5 healthy lifestyle factors), intermediate (3 healthy lifestyle factors), and unfavorable (0-2 healthy lifestyle factors) groups. Cox proportional hazards regression model was used to estimate the hazard ratios (HR) and 95% confidence interval (CI) for their associations. RESULTS: During the 12-year follow-up, 707 cases with CD and 1576 cases with UC were diagnosed in the UK Biobank cohort. Genetic risk and unhealthy lifestyle categories were monotonically associated with CD and UC risk with no multiplicative interaction between them. The HR of CD and UC were 2.24 (95% CI 1.75-2.86) and 2.15 (95% CI 1.82-2.53) for those with a high genetic risk, respectively. The HR of CD and UC for individuals with an unfavorable lifestyle were 1.94 (95% CI 1.61-2.33) and 1.98 (95% CI 1.73-2.27), respectively. The HR of individuals with a high genetic risk but a favorable lifestyle (2.33, 95% CI 1.58-3.44 for CD, and 2.05, 95% CI 1.58-2.66 for UC) were reduced nearly by half, compared with those with a high genetic risk but an unfavorable lifestyle (4.40, 95% CI 2.91-6.66 for CD and 4.44, 95% CI 3.34-5.91 for UC). DISCUSSION: Genetic and lifestyle factors were independently associated with susceptibility to incident CD and UC. Adherence to a favorable lifestyle was associated with a nearly 50% lower risk of CD and UC among participants at a high genetic risk.
Assuntos
Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Adulto , Humanos , Estudos Prospectivos , Doenças Inflamatórias Intestinais/complicações , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/genética , Colite Ulcerativa/complicações , Doença de Crohn/epidemiologia , Doença de Crohn/genética , Doença de Crohn/complicações , Fatores de Risco , Estilo de Vida , IncidênciaRESUMO
Vitamin D deficiency is associated with risk of several common cancers, including colorectal cancer (CRC). Here we have utilized patient derived epithelial organoids (ex vivo) and CRC cell lines (in vitro) to show that calcitriol (1,25OHD) increased the expression of the CRC tumor suppressor gene, CDH1, at both the transcript and protein level. Whole genome expression analysis demonstrated significant differential expression of a further six genes after 1,25OHD treatment, including genes with established links to carcinogenesis GADD45, EFTUD1 and KIAA1199. Furthermore, gene ontologies relevant to carcinogenesis were enriched by 1,25OHD treatment (e.g., 'regulation of Wnt signaling pathway', 'regulation of cell death'), with common enriched processes across in vitro and ex vivo cultures including 'negative regulation of cell proliferation', 'regulation of cell migration' and 'regulation of cell differentiation'. Our results identify genes and pathways that are modifiable by calcitriol that have links to CRC tumorigenesis. Hence the findings provide potential mechanism to the epidemiological and clinical trial data indicating a causal association between vitamin D and CRC. We suggest there is strong rationale for further well-designed trials of vitamin D supplementation as a novel CRC chemopreventive and chemotherapeutic agent.
Assuntos
Antineoplásicos/farmacologia , Carcinogênese/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Neoplasias/biossíntese , Neoplasias/metabolismo , Transcriptoma/efeitos dos fármacos , Vitamina D/análogos & derivados , Células CACO-2 , Células HCT116 , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Vitamina D/farmacologiaRESUMO
Epidemiological evidence is consistent with a protective effect of vitamin D against colorectal cancer (CRC), but the observed strong associations are open to confounders and potential reverse causation. Previous Mendelian randomisation (MR) studies were limited by poor genetic instruments and inadequate statistical power. Moreover, whether genetically higher CRC risk can influence vitamin D level, namely the reverse causation, still remains unknown. Herein, we report the first bidirectional MR study. We employed 110 newly identified genetic variants as proxies for vitamin D to obtain unconfounded effect estimates on CRC risk in 26 397 CRC cases and 41 481 controls of European ancestry. To test for reserve causation, we estimated effects of 115 CRC-risk variants on vitamin D level among 417 580 participants from the UK Biobank. The causal association was estimated using the random-effect inverse-variance weighted (IVW) method. We found no significant causal effect of vitamin D on CRC risk [IVW estimate odds ratio: 0.97, 95% confidence interval (CI) = 0.88-1.07, P = .565]. Similarly, no significant reverse causal association was identified between genetically increased CRC risk and vitamin D levels (IVW estimate ß: -0.002, 95% CI = -0.008 to 0.004, P = .543). Stratified analysis by tumour sites did not identify significant causal associations in either direction between vitamin D and colon or rectal cancer. Despite the improved statistical power of this study, we found no evidence of causal association of either direction between circulating vitamin D and CRC risk. Significant associations reported by observational studies may be primarily driven by unidentified confounders.
Assuntos
Neoplasias Colorretais/epidemiologia , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana/estatística & dados numéricos , Polimorfismo de Nucleotídeo Único , Vitamina D/sangue , Vitaminas/sangue , Estudos de Casos e Controles , Causalidade , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Seguimentos , Humanos , Prognóstico , Fatores de Risco , Reino Unido/epidemiologiaRESUMO
Alcohol consumption is thought to be one of the modifiable risk factors for colorectal cancer (CRC). However, the causality and mechanisms by which alcohol exerts its carcinogenic effect are unclear. We evaluated the association between alcohol consumption and CRC risk by analyzing data from 32 cohort studies and conducted two-sample Mendelian randomization (MR) analysis to examine for casual relationship. To explore the effect of alcohol related DNA methylation on CRC risk, we performed an epigenetic MR analysis with data from an epigenome-wide association study (EWAS). We additionally performed gene-alcohol interaction analysis nested in the UK Biobank to assess effect modification between alcohol consumption and susceptibility genes. We discovered distinct effects of alcohol on CRC incidence and mortality from the meta-analyses, and genetic predisposition to alcohol drinking was causally associated with an increased CRC risk (OR = 1.79, 95% CI: 1.23-2.61) using two-sample MR approaches. In epigenetic MR analysis, two alcohol-related CpG sites (cg05593667 and cg10045354 mapped to COLCA1/COLCA2 gene) were identified causally associated with an increased CRC risk (P < 8.20 × 10-4 ). Gene-alcohol interaction analysis revealed that carriage of the risk allele of the eQTL (rs3087967) and mQTL (rs11213823) polymorphism of COLCA1/COLCA2 would interact with alcohol consumption to increase CRC risk (PInteraction = .027 and PInteraction = .016). Our study provides comprehensive evidence to elucidate the role of alcohol in CRC and highlights that the pathogenic effect of alcohol on CRC could be partly attributed to DNA methylation by regulating the expression of COLCA1/COLCA2 gene.
Assuntos
Consumo de Bebidas Alcoólicas , Neoplasias Colorretais , Metilação de DNA , Análise da Randomização Mendeliana , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/metabolismo , Estudos de Coortes , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana/métodos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Associations between colorectal cancer (CRC) and other health outcomes have been reported, but these may be subject to biases, or due to limitations of observational studies. METHODS: We set out to determine whether genetic predisposition to CRC is also associated with the risk of other phenotypes. Under the phenome-wide association study (PheWAS) and tree-structured phenotypic model (TreeWAS), we studied 334,385 unrelated White British individuals (excluding CRC patients) from the UK Biobank cohort. We generated a polygenic risk score (PRS) from CRC genome-wide association studies as a measure of CRC risk. We performed sensitivity analyses to test the robustness of the results and searched the Danish Disease Trajectory Browser (DTB) to replicate the observed associations. RESULTS: Eight PheWAS phenotypes and 21 TreeWAS nodes were associated with CRC genetic predisposition by PheWAS and TreeWAS, respectively. The PheWAS detected associations were from neoplasms and digestive system disease group (e.g. benign neoplasm of colon, anal and rectal polyp and diverticular disease). The results from the TreeWAS corroborated the results from the PheWAS. These results were replicated in the observational data within the DTB. CONCLUSIONS: We show that benign colorectal neoplasms share genetic aetiology with CRC using PheWAS and TreeWAS methods. Additionally, CRC genetic predisposition is associated with diverticular disease.
Assuntos
Neoplasias Colorretais/patologia , Estudo de Associação Genômica Ampla/métodos , Fenômica/métodos , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Bancos de Espécimes Biológicos , Neoplasias Colorretais/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Reino UnidoRESUMO
BACKGROUND: Substantial evidence indicates that dysbiosis of the gut microbial community is associated with colorectal neoplasia. This review aims to systematically summarise the microbial markers associated with colorectal neoplasia and to assess their predictive performance. METHODS: A comprehensive literature search of MEDLINE and EMBASE databases was performed to identify eligible studies. Observational studies exploring the associations between microbial biomarkers and colorectal neoplasia were included. We also included prediction studies that constructed models using microbial markers to predict CRC and adenomas. Risk of bias for included observational and prediction studies was assessed. RESULTS: Forty-five studies were included to assess the associations between microbial markers and colorectal neoplasia. Nine faecal microbiotas (i.e., Fusobacterium, Enterococcus, Porphyromonas, Salmonella, Pseudomonas, Peptostreptococcus, Actinomyces, Bifidobacterium and Roseburia), two oral pathogens (i.e., Treponema denticola and Prevotella intermedia) and serum antibody levels response to Streptococcus gallolyticus subspecies gallolyticus were found to be consistently associated with colorectal neoplasia. Thirty studies reported prediction models using microbial markers, and 83.3% of these models had acceptable-to-good discrimination (AUROC > 0.75). The results of predictive performance were promising, but most of the studies were limited to small number of cases (range: 9-485 cases) and lack of independent external validation (76.7%). CONCLUSIONS: This review provides insight into the evidence supporting the association between different types of microbial species and their predictive value for colorectal neoplasia. Prediction models developed from case-control studies require further external validation in high-quality prospective studies. Further studies should assess the feasibility and impact of incorporating microbial biomarkers in CRC screening programme.
Assuntos
Adenoma , Neoplasias Colorretais , Biomarcadores , Neoplasias Colorretais/diagnóstico , Disbiose , Humanos , Estudos ProspectivosRESUMO
Human protein glycosylation is a complex process, and its in vivo regulation is poorly understood. Changes in glycosylation patterns are associated with many human diseases and conditions. Understanding the biological determinants of protein glycome provides a basis for future diagnostic and therapeutic applications. Genome-wide association studies (GWAS) allow to study biology via a hypothesis-free search of loci and genetic variants associated with a trait of interest. Sixteen loci were identified by three previous GWAS of human plasma proteome N-glycosylation. However, the possibility that some of these loci are false positives needs to be eliminated by replication studies, which have been limited so far. Here, we use the largest set of samples so far (4802 individuals) to replicate the previously identified loci. For all but one locus, the expected replication power exceeded 95%. Of the 16 loci reported previously, 15 were replicated in our study. For the remaining locus (near the KREMEN1 gene), the replication power was low, and hence, replication results were inconclusive. The very high replication rate highlights the general robustness of the GWAS findings as well as the high standards adopted by the community that studies genetic regulation of protein glycosylation. The 15 replicated loci present a good target for further functional studies. Among these, eight loci contain genes encoding glycosyltransferases: MGAT5, B3GAT1, FUT8, FUT6, ST6GAL1, B4GALT1, ST3GAL4 and MGAT3. The remaining seven loci offer starting points for further functional follow-up investigation into molecules and mechanisms that regulate human protein N-glycosylation in vivo.
Assuntos
Glicosiltransferases/metabolismo , Proteínas de Membrana/metabolismo , Estudos de Coortes , Biologia Computacional , Glicosilação , Glicosiltransferases/química , Glicosiltransferases/genética , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/genética , Polissacarídeos/metabolismoRESUMO
Previous studies using additive genetic models failed to identify robust evidence of associations between colorectal cancer (CRC) risk variants and survival outcomes. However, additive models can be prone to false negative detection if the underlying inheritance mode is recessive. Here, we tested all currently known CRC-risk variants (n = 129) in a discovery analysis of 5675 patients from a Scottish cohort. Significant associations were then validated in 2474 CRC cases from UK Biobank. We found that the TT genotype of the intron variant rs7495132 in the CRTC3 gene was associated with clinically relevant poorer CRC-specific survival in both the discovery (hazard ratio [HR] = 1.97, 95% confidence interval [CI] = 1.41-2.74, P = 6.1 × 10-5 ) and validation analysis (HR = 1.69, 95% CI = 1.03-2.79, P = .038). In addition, the GG genotype of rs10161980 (intronic variant of AL139383.1 lncRNA) was associated with worse overall survival in the discovery cohort (HR = 1.24, 95% CI = 1.10-1.39, P = 3.4 × 10-4 ) and CRC-specific survival in the validation cohort (HR = 1.26, 95% CI = 1.01-1.56, P = .040). Our findings show that common genetic risk factors can also influence CRC survival outcome.
Assuntos
Neoplasias Colorretais/mortalidade , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , Idoso , Bancos de Espécimes Biológicos , Neoplasias Colorretais/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Escócia , Análise de SobrevidaRESUMO
Site-specific variation in colorectal cancer (CRC) incidence, biology and prognosis are poorly understood. We sought to determine whether common genetic variants influencing CRC risk might exhibit topographical differences on CRC risk through regional differences in effects on gene expression in the large bowel mucosa. We conducted a site-specific genetic association study (10 630 cases, 31 331 controls) to identify whether established risk variants exert differential effects on risk of proximal, compared to distal CRC. We collected normal colorectal mucosa and blood from 481 subjects and assessed mucosal gene expression using Illumina HumanHT-12v4 arrays in relation to germline genotype. Expression quantitative trait loci (eQTLs) were explored by anatomical location of sampling. The rs3087967 genotype (chr11q23.1 risk variant) exhibited significant site-specific effects-risk of distal CRC (odds ratio [OR] = 1.20, P = 8.20 × 10-20 ) with negligible effects on proximal CRC risk (OR = 1.05, P = .10). Expression of 1261 genes differed between proximal and distal colonic mucosa (top hit PRAC gene, fold-difference = 10, P = 3.48 × 10-57 ). In eQTL studies, rs3087967 genotype was associated with expression of 8 cis- and 21 trans-genes. Four of these (AKAP14, ADH5P4, ASGR2, RP11-342M1.7) showed differential effects by site, with strongest trans-eQTL signals in proximal colonic mucosa (eg, AKAP14, beta = 0.61, P = 5.02 × 10-5 ) and opposite signals in distal mucosa (AKAP14, beta = -0.17, P = .04). In summary, genetic variation at the chr11q23.1 risk locus imparts greater risk of distal rather than proximal CRC and exhibits site-specific differences in eQTL effects in normal mucosa. Topographical differences in genomic control over gene expression relevant to CRC risk may underlie site-specific variation in CRC. Results may inform individualised CRC screening programmes.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Mucosa Intestinal/metabolismo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Transcriptoma , Adulto JovemRESUMO
Glycosylation is a common post-translational modification of proteins. Glycosylation is associated with a number of human diseases. Defining genetic factors altering glycosylation may provide a basis for novel approaches to diagnostic and pharmaceutical applications. Here we report a genome-wide association study of the human blood plasma N-glycome composition in up to 3811 people measured by Ultra Performance Liquid Chromatography (UPLC) technology. Starting with the 36 original traits measured by UPLC, we computed an additional 77 derived traits leading to a total of 113 glycan traits. We studied associations between these traits and genetic polymorphisms located on human autosomes. We discovered and replicated 12 loci. This allowed us to demonstrate an overlap in genetic control between total plasma protein and IgG glycosylation. The majority of revealed loci contained genes that encode enzymes directly involved in glycosylation (FUT3/FUT6, FUT8, B3GAT1, ST6GAL1, B4GALT1, ST3GAL4, MGAT3 and MGAT5) and a known regulator of plasma protein fucosylation (HNF1A). However, we also found loci that could possibly reflect other more complex aspects of glycosylation process. Functional genomic annotation suggested the role of several genes including DERL3, CHCHD10, TMEM121, IGH and IKZF1. The hypotheses we generated may serve as a starting point for further functional studies in this research area.
Assuntos
Fucosiltransferases/genética , Glicosiltransferases/genética , Polissacarídeos/sangue , Cromatografia Líquida de Alta Pressão , Estudos de Coortes , Fucosiltransferases/sangue , Fucosiltransferases/química , Estudo de Associação Genômica Ampla , Glucuronosiltransferase/sangue , Glucuronosiltransferase/química , Glicosilação , Fator 1-alfa Nuclear de Hepatócito/sangue , Fator 1-alfa Nuclear de Hepatócito/química , Humanos , Imunoglobulina G/metabolismo , Proteínas de Membrana/metabolismo , Polimorfismo Genético , Locos de Características QuantitativasRESUMO
BACKGROUND: We conducted a Mendelian randomisation (MR) study to investigate whether physical activity (PA) causes a reduction of colorectal cancer risk and to understand the contributions of effects mediated through changes in body fat. METHODS: Common genetic variants associated with self-reported moderate-to-vigorous PA (MVPA), acceleration vector magnitude PA (AMPA) and sedentary time were used as instrumental variables. To control for confounding effects of obesity, we included instrumental variables for body mass index (BMI), body fat percentage, waist circumference and arm, trunk and leg fat ratios. We analysed the effect of these instrumental variables in a colorectal cancer genome-wide association study comprising 31,197 cases and 61,770 controls of European ancestry by applying two-sample and multivariable MR study designs. RESULTS: We found decreased colorectal cancer risk for genetically represented measures of MVPA and AMPA that were additional to effects mediated through genetic measures of obesity. Odds ratio and 95% confidence interval (CI) per standard deviation increase in MVPA and AMPA was 0.56 (0.31, 1.01) and 0.60 (0.41, 0.88), respectively. No association has been found between sedentary time and colorectal cancer risk. The proportion of effect mediated through BMI was 2% (95% CI: 0, 14) and 32% (95% CI: 12, 46) for MVPA and AMPA, respectively. CONCLUSION: These findings provide strong evidence to reinforce public health measures on preventing colorectal cancer that promote PA at a population level regardless of body fatness.
Assuntos
Adiposidade , Índice de Massa Corporal , Neoplasias Colorretais/epidemiologia , Exercício Físico , Análise da Randomização Mendeliana/métodos , Obesidade/complicações , Comportamento Sedentário , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/genética , Europa (Continente) , Estudo de Associação Genômica Ampla , Humanos , Obesidade/epidemiologia , Obesidade/genética , Prognóstico , Fatores de RiscoRESUMO
AIM: The dramatic curtailment of endoscopy and CT colonography capacity during the coronavirus pandemic has adversely impacted timely diagnosis of colorectal cancer (CRC). We describe a rapidly implemented COVID-adapted diagnostic pathway to mitigate risk and maximize cancer diagnosis in patients referred with symptoms of suspected CRC. METHOD: The 'COVID-adapted pathway' integrated multiple quantitative faecal immunochemical tests (qFIT) to enrich for significant colorectal disease with judicious use of CT with oral contrast to detect gross pathology. Patients reporting 'high-risk' symptoms were triaged to qFIT+CT and the remainder underwent an initial qFIT to inform subsequent investigation. Demographic and clinical data were prospectively collected. Outcomes comprised cancer detection frequency. RESULTS: Overall, 422 patients (median age 64 years, 220 women) were triaged using this pathway. Most (84.6%) were referred as 'urgent suspicious of cancer'. Of the 422 patients, 202 (47.9%) were triaged to CT and qFIT, 211 (50.0%) to qFIT only, eight (1.9%) to outpatient clinic and one to colonoscopy. Fifteen (3.6%) declined investigation and seven (1.7%) were deemed unfit. We detected 13 cancers (3.1%), similar to the mean cancer detection rate from all referrals in 2017-2019 (3.3%). Compared with the period 1 April-31 May in 2017-2019, we observed a 43% reduction in all primary care referrals (1071 referrals expected reducing to 609). CONCLUSION: This COVID-adapted pathway mitigated the adverse effects on diagnostic capacity and detected cancer at the expected rate within those referred. However, the overall reduction in the number of referrals was substantial. The described risk-mitigating measures could be a useful adjunct whilst standard diagnostic services remain constrained due to the ongoing pandemic.
Assuntos
COVID-19 , Neoplasias Colorretais , Idoso , Colonoscopia , Neoplasias Colorretais/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sangue Oculto , SARS-CoV-2 , TriagemRESUMO
Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. The quantification of an individual's lifetime risk of gastrointestinal cancer may incorporate clinical and molecular data, and depends on accurate phenotypic assessment and genetic diagnosis. In turn this may facilitate targeted risk-reducing interventions, including endoscopic surveillance, preventative surgery and chemoprophylaxis, which provide opportunities for cancer prevention. This guideline is an update from the 2010 British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland (BSG/ACPGBI) guidelines for colorectal screening and surveillance in moderate and high-risk groups; however, this guideline is concerned specifically with people who have increased lifetime risk of CRC due to hereditary factors, including those with Lynch syndrome, polyposis or a family history of CRC. On this occasion we invited the UK Cancer Genetics Group (UKCGG), a subgroup within the British Society of Genetic Medicine (BSGM), as a partner to BSG and ACPGBI in the multidisciplinary guideline development process. We also invited external review through the Delphi process by members of the public as well as the steering committees of the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE). A systematic review of 10 189 publications was undertaken to develop 67 evidence and expert opinion-based recommendations for the management of hereditary CRC risk. Ten research recommendations are also prioritised to inform clinical management of people at hereditary CRC risk.
Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/terapia , Vigilância da População , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/prevenção & controle , Polipose Adenomatosa do Colo/terapia , Colonoscopia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/prevenção & controle , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/prevenção & controle , Neoplasias Colorretais Hereditárias sem Polipose/terapia , DNA Glicosilases/genética , Saúde da Família , Humanos , Polipose Intestinal/congênito , Polipose Intestinal/genética , Polipose Intestinal/terapia , Irlanda , Estilo de Vida , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Síndrome de Peutz-Jeghers/genética , Síndrome de Peutz-Jeghers/terapia , Encaminhamento e Consulta/normas , Fatores de Risco , Reino UnidoRESUMO
OBJECTIVE: To provide an understanding of the role of common genetic variations in colorectal cancer (CRC) risk, we report an updated field synopsis and comprehensive assessment of evidence to catalogue all genetic markers for CRC (CRCgene2). DESIGN: We included 869 publications after parallel literature review and extracted data for 1063 polymorphisms in 303 different genes. Meta-analyses were performed for 308 single nucleotide polymorphisms (SNPs) in 158 different genes with at least three independent studies available for analysis. Scottish, Canadian and Spanish data from genome-wide association studies (GWASs) were incorporated for the meta-analyses of 132 SNPs. To assess and classify the credibility of the associations, we applied the Venice criteria and Bayesian False-Discovery Probability (BFDP). Genetic associations classified as 'positive' and 'less-credible positive' were further validated in three large GWAS consortia conducted in populations of European origin. RESULTS: We initially identified 18 independent variants at 16 loci that were classified as 'positive' polymorphisms for their highly credible associations with CRC risk and 59 variants at 49 loci that were classified as 'less-credible positive' SNPs; 72.2% of the 'positive' SNPs were successfully replicated in three large GWASs and the ones that were not replicated were downgraded to 'less-credible' positive (reducing the 'positive' variants to 14 at 11 loci). For the remaining 231 variants, which were previously reported, our meta-analyses found no evidence to support their associations with CRC risk. CONCLUSION: The CRCgene2 database provides an updated list of genetic variants related to CRC risk by using harmonised methods to assess their credibility.
Assuntos
Neoplasias Colorretais/genética , Polimorfismo de Nucleotídeo Único , Proteínas Adaptadoras de Transdução de Sinal/genética , Antígenos CD/genética , Proteína Morfogenética Óssea 2/genética , Caderinas/genética , DNA Glicosilases/genética , Estudos de Associação Genética , Loci Gênicos , Humanos , Proteína Smad7/genética , Telomerase/genética , Fator de Crescimento Transformador beta1/genéticaRESUMO
Increasing numbers of common genetic variants associated with colorectal cancer (CRC) have been identified. Our study aimed to determine whether risk prediction based on common genetic variants might enable stratification for CRC risk. Meta-analysis of 11 genome-wide association studies comprising 16 871 cases and 26 328 controls was performed to capture CRC susceptibility variants. Genetic prediction models with several candidate polygenic risk scores (PRSs) were generated from Scottish CRC case-control studies (6478 cases and 11 043 controls) and the score with the best performance was then tested in UK Biobank (UKBB) (4800 cases and 20 287 controls). A weighted PRS of 116 CRC single nucleotide polymorphisms (wPRS116 ) was found with the best predictive performance, reporting a c-statistics of 0.60 and an odds ratio (OR) of 1.46 (95% confidence interval [CI] = 1.41-1.50, per SD increase) in Scottish data set. The predictive performance of this wPRS116 was consistently validated in UKBB data set with c-statistics of 0.61 and an OR of 1.49 (95% CI = 1.44-1.54, per SD increase). Modeling the levels of PRS with age and sex in the general UK population shows that employing genetic risk profiling can achieve a moderate degree of risk discrimination that could be helpful to identify a subpopulation with higher CRC risk due to genetic susceptibility.