scholarly journals The Role of Colorectal Cancer Risk Chromosomal Regions in Colombian Admixed Populations

2018 ◽  
Vol 4 (Supplement 2) ◽  
pp. 207s-207s
Author(s):  
A. Criollo-Rayo ◽  
M. Bohórquez ◽  
P. Lott ◽  
A. Carracedo ◽  
I. Tomlinson ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Susceptibility ◽  
Association Studies ◽  
Demographic History ◽  
Recessive Model ◽  
Genome Wide Association Studies ◽  
Increased Risk ◽  
Risk Snps ◽  
Population Demographic

Background: Several colorectal cancer susceptibility disease loci have been discovered through genome-wide association studies. However most of the variants were originally identified in Caucasian populations. Aim: To analyze the role of 20 known risk SNPs for colorectal cancer. Methods: Given that linkage disequilibrium is highly dependent on population demographic history and admixture background, we studied 20 risk SNPs in a pooled sample of 955 cases and 968 controls from admixed populations in Colombia. Results: The replication was reached for 11 out of 20 nominally associated SNPs; with allelic odds ratios (OR) ranging from 1.14 to 1.41, indicating a minimal increase in risk individually, however coinheritance of those SNPs resulted in an overall OR = 5.4 (95% CI: 3.052-9.731, P = 1.16E−08). Most of the variants followed a recessive model consistent with significant homozygous ORs distributed between 1.3 and 1.65. Among the most associated markers we found: rs4939827 (18q21.1, P = 7.35E−6), rs10411210 (19q13.11, P = 0.001), rs10795668 (10p14, P = 0.0024), rs4444235 (14q.2.2, P = 0.005), rs961253 (20p12.3, P = 0.006), rs16892766 (8q23.3, P = 0.011) and rs1050547 (8q24.21, P = 0.017). Conclusion: Our findings in Colombia have addressed the admixture and how this has influenced the risk associated with the known/unknown colorectal cancer regions, providing a comprehensive vision about several CRC-susceptibility SNPs identified in European populations, which also resulted, associated with an increased risk to CRC in the Colombian population, even though frequency and genetic structure differences accounted for those nonreplicated SNPs.

Known colorectal cancer susceptibility loci and survival after colorectal cancer diagnosis.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 394-394 ◽  
Author(s):  
Amanda Phipps ◽  
Xabier Garcia-Albeniz ◽  
Carolyn Hutter ◽  
Emily White ◽  
Charles S. Fuchs ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Fixed Effects ◽  
Cancer Susceptibility ◽  
Association Studies ◽  
Cox Proportional Hazards ◽  
Health Study ◽  
Genome Wide Association Studies ◽  
Increased Risk

394 Background: Beyond clinicopathologic stage, there are few established markers of prognosis in colorectal cancer (CRC). Recent genome-wide association studies have identified 17 germline single nucleotide polymorphisms (SNPs) significantly associated with incident CRC. However, it is unclear if these CRC susceptibility SNPs influence survival after CRC diagnosis. Although the functionality of many of these SNPs remains unknown, a few, including rs4939827 in SMAD7, map to genes with plausible biological mechanisms associated with both cancer risk and prognosis. We examined 17 CRC susceptibility SNPs in relation to survival after CRC diagnosis. Methods: We genotyped 2,611 men and women enrolled in five prospective cohort studies who were diagnosed with invasive CRC during study follow-up: the Physicians’ Health Study (N=281), Health Professionals Follow-up Study (N=268), Nurses’ Health Study (N=367), Vitamins and Lifestyle Study (N=281), and the Women’s Health Initiative (N=1414). Analyses were limited to Caucasians with known vital status, cause of death, and survival time. We used Cox proportional hazards regression to assess associations between each SNP and CRC-specific and overall survival in study-specific models adjusted for age, sex, and stage; SNPs were modeled additively to reflect associations per copy of the minor allele. Study-specific results were combined via fixed-effects meta-analysis. Results: The G allele in rs4939827 was associated with poorer CRC-specific survival [hazard ratio (HR)=1.16, p=0.02] and overall survival (HR=1.13, p=0.03) in CRC patients. The A alleles in rs10795668 and in rs4925386 were associated with a 1.14-fold increased risk of overall mortality (both p-values=0.03) but not CRC-specific mortality. Other evaluated SNPs were not associated with survival. Conclusions: Genetic variation in rs4939827 (SMAD7) is associated with CRC-specific and overall survival. These results suggest that SMAD7 may have a role in CRC progression, and provide proof-of-principle that common germline variation may provide prognostic information beyond traditional considerations such as stage.

scholarly journals Genetic Variants in SNCA and the Risk of Sporadic Parkinson’s Disease and Clinical Outcomes: A Review

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Clarissa Loureiro das Chagas Campêlo ◽  
Regina Helena Silva
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Environmental Factors ◽  
Clinical Outcomes ◽  
Association Studies ◽  
Clinical Aspects ◽  
Genome Wide Association Studies ◽  
Snca Gene ◽  
Increased Risk

There is increasing evidence of the contribution of genetic susceptibility to the etiology of Parkinson’s disease (PD). Genetic variations in the SNCA gene are well established by linkage and genome-wide association studies. Positive associations of single nucleotide polymorphisms (SNPs) in SNCA and increased risk for PD were found. However, the role of SNCA variants in individual traits or phenotypes of PD is unknown. Here, we reviewed the current literature and identified 57 studies, performed in fourteen different countries, that investigated SNCA variants and susceptibility to PD. We discussed the findings based on environmental factors, history of PD, clinical outcomes, and ethnicity. In conclusion, SNPs within the SNCA gene can modify the susceptibility to PD, leading to increased or decreased risk. The risk associations of some SNPs varied among samples. Of notice, no studies in South American or African populations were found. There is little information about the effects of these variants on particular clinical aspects of PD, such as motor and nonmotor symptoms. Similarly, evidence of possible interactions between SNCA SNPs and environmental factors or disease progression is scarce. There is a need to expand the clinical applicability of these data as well as to investigate the role of SNCA SNPs in populations with different ethnic backgrounds.

scholarly journals Potential Role of Glucose Transporters in Glucose Homeostasis: a Narrative Review

2021 ◽  
Vol 9 (1) ◽  
pp. 82-85
Author(s):  
Muslim Bin Aqeel ◽  
Sana Ashiq ◽  
Mayyda Asif Bajwa ◽  
Kanwal Ashiq
Keyword(s):  
Glucose Homeostasis ◽  
Glucose Transporter ◽  
Association Studies ◽  
Receptor Gene ◽  
Glycogen Storage Disease Type ◽  
Narrative Review ◽  
Genome Wide Association Studies ◽  
Glucose Transporter 2 ◽  
Increased Risk

Background: The GLUT2 (glucose transporter 2) is a glucose sensitive receptor gene found in the liver, pancreas, and sometimes in the CNS. The experiments conducted on the genetically modified mice revealed their role in the different regulatory mechanisms. Objective: The current narrative review aims to elucidate the role of GLUT2 in glucose homeostasis. Methods: The recent related articles were reviewed with the help of different databases including PubMed, Google Scholar, Springer link, and Science direct. To ensure the credibility of data, articles published only in indexed journals were considered. Results: In the liver (hepatocytes), it’s reported that there is an unsuspected glucose pathway (output) that is dependent on the membrane mechanism is in progress. In humans, due to the mutation in the GLUT2 gene, there is a syndrome known as “Fanconi–Bickel syndrome” which dictates a glycogen storage disease type 11 disease characterized by kidney and liver disorders. Conclusion: It is concluded from the genome-wide association studies that the genetic mutations in GLUT2 result in an increased risk of high cholesterol, cardiovascular diseases (CVDs), and fasting hyperglycemia.

scholarly journals Breed-Predispositions to Cancer in Pedigree Dogs

2013 ◽  
Vol 2013 ◽  
pp. 1-23 ◽  
Author(s):  
Jane M. Dobson
Keyword(s):  
Cancer Susceptibility ◽  
Association Studies ◽  
Molecular Genetic ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Complex Disorders ◽  
Genome Wide ◽  
Increased Risk ◽  
Purebred Dogs ◽  
Limited Genetic Diversity

Cancer is a common problem in dogs and although all breeds of dog and crossbred dogs may be affected, it is notable that some breeds of pedigree dogs appear to be at increased risk of certain types of cancer suggesting underlying genetic predisposition to cancer susceptibility. Although the aetiology of most cancers is likely to be multifactorial, the limited genetic diversity seen in purebred dogs facilitates genetic linkage or association studies on relatively small populations as compared to humans, and by using newly developed resources, genome-wide association studies in dog breeds are proving to be a powerful tool for unravelling complex disorders. This paper will review the literature on canine breed susceptibility to histiocytic sarcoma, osteosarcoma, haemangiosarcoma, mast cell tumours, lymphoma, melanoma, and mammary tumours including the recent advances in knowledge through molecular genetic, cytogenetic, and genome wide association studies.

scholarly journals Scarless genome editing reveals risk SNP rs6983267-G and lncRNA CCAT2 dictate targetable PI3K signaling dependence in WNT-dysregulated CRC

2021 ◽  
Author(s):  
Nicole B. Coggins ◽  
Henriette O’Geen ◽  
Paul C. Lott ◽  
David J. Segal ◽  
Luis Carvajal Carmona
Keyword(s):  
Risk Allele ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Growth Factor Signaling ◽  
Cellular Models ◽  
Genome Wide ◽  
Potential Biomarker ◽  
Increased Risk ◽  
Hct 116

Abstract Genome-wide association studies have identified numerous loci associated with increased risk for colorectal cancer (CRC), including 8q24.21 which contains a known enhancer of proto-oncogene MYC . However, the role of candidate functional SNP rs6983267 within this locus remains unclear. Here, we generate isogenic cellular models of risk SNP rs6983267 in human CRC line, HCT-116. Comprehensive molecular characterization reveals risk allele-G drives enhancer DNA contacts with downstream regions that include MYC . Absence of risk allele leads to activation of lncRNA CCAT2 . Rather than changes in MYC expression, we observe activation of alternative growth factor signaling pathways with loss of both risk allele and CCAT2 expression. Analysis of TCGA CRC cases demonstrates low CCAT2 expression combined with non-risk rs6983267 genotype correlate with higher frequency of PI3K mutations in CRC patients displaying WNT dysregulation. Together, these provide a potential biomarker for therapeutically targetable PI3K dysregulation in CRC and application in cancer precision medicine.

scholarly journals Colorectal cancer susceptibility variants and risk of conventional adenomas and serrated polyps: results from three cohort studies

2019 ◽  
Vol 49 (1) ◽  
pp. 259-269 ◽  
Author(s):  
Dong Hang ◽  
Amit D Joshi ◽  
Xiaosheng He ◽  
Andrew T Chan ◽  
Manol Jovani ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cohort Studies ◽  
Genetic Variants ◽  
Association Studies ◽  
Genetic Risk Score ◽  
Genome Wide Association Studies ◽  
Serrated Polyps ◽  
Common Genetic Variants ◽  
Increased Risk ◽  
Weighted Genetic Risk Score

Abstract Background Increasing evidence suggests that conventional adenomas (CAs) and serrated polyps (SPs) represent two distinct groups of precursor lesions for colorectal cancer (CRC). The influence of common genetic variants on risk of CAs and SPs remain largely unknown. Methods Among 27 426 participants within three prospective cohort studies, we created a weighted genetic risk score (GRS) based on 40 CRC-related single nucleotide polymorphisms (SNPs) identified in previous genome-wide association studies; and we examined the association of GRS (per one standard deviation increment) with risk of CAs, SPs and synchronous CAs and SPs, by multivariable logistic regression. We also analysed individual variants in the secondary analysis. Results During 18–20 years of follow-up, we documented 2952 CAs, 1585 SPs and 794 synchronous CAs and SPs. Higher GRS was associated with increased risk of CAs [odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.12-1.21] and SPs (OR = 1.09, 95% CI: 1.03-1.14), with a stronger association for CAs than SPs (Pheterogeneity=0.01). An even stronger association was found for patients with synchronous CAs and SPs (OR = 1.32), advanced CAs (OR = 1.22) and multiple CAs (OR = 1.25). Different sets of variants were associated with CAs and SPs, with a Spearman correlation coefficient of 0.02 between the ORs associating the 40 SNPs with the two lesions. After correcting for multiple testing, three variants were associated with CAs (rs3802842, rs6983267 and rs7136702) and two with SPs (rs16892766 and rs4779584). Conclusions Common genetic variants play a potential role in the conventional and serrated pathways of CRC. Different sets of variants are identified for the two pathways, further supporting the aetiological heterogeneity of CRC.

scholarly journals Nongenic cancer-risk SNPs affect oncogenes, tumour-suppressor genes, and immune function

2019 ◽  
Vol 122 (4) ◽  
pp. 569-577 ◽  
Author(s):  
Maud Fagny ◽  
John Platig ◽  
Marieke Lydia Kuijjer ◽  
Xihong Lin ◽  
John Quackenbush
Keyword(s):  
Cancer Risk ◽  
Association Studies ◽  
Tumour Suppressor ◽  
Tumour Suppressor Genes ◽  
Eqtl Analysis ◽  
Genome Wide Association Studies ◽  
Suppressor Genes ◽  
Tissue Specific ◽  
Increased Risk ◽  
Risk Snps

Abstract Background Genome-wide association studies (GWASes) have identified many noncoding germline single-nucleotide polymorphisms (SNPs) that are associated with an increased risk of developing cancer. However, how these SNPs affect cancer risk is still largely unknown. Methods We used a systems biology approach to analyse the regulatory role of cancer-risk SNPs in thirteen tissues. By using data from the Genotype-Tissue Expression (GTEx) project, we performed an expression quantitative trait locus (eQTL) analysis. We represented both significant cis- and trans-eQTLs as edges in tissue-specific eQTL bipartite networks. Results Each tissue-specific eQTL network is organised into communities that group sets of SNPs and functionally related genes. When mapping cancer-risk SNPs to these networks, we find that in each tissue, these SNPs are significantly overrepresented in communities enriched for immune response processes, as well as tissue-specific functions. Moreover, cancer-risk SNPs are more likely to be ‘cores’ of their communities, influencing the expression of many genes within the same biological processes. Finally, cancer-risk SNPs preferentially target oncogenes and tumour-suppressor genes, suggesting that they may alter the expression of these key cancer genes. Conclusions This approach provides a new way of understanding genetic effects on cancer risk and provides a biological context for interpreting the results of GWAS cancer studies.

scholarly journals Characterization of population-based variation and putative functional elements for the multiple-cancer susceptibility loci at 5p15.33

F1000Research ◽  
2014 ◽  
Vol 3 ◽  
pp. 231
Author(s):  
Lisa Mirabello ◽  
Charles C. Chung ◽  
Meredith Yeager ◽  
Sharon A Savage
Keyword(s):  
Cancer Susceptibility ◽  
Association Studies ◽  
Population Based ◽  
Genome Wide Association Studies ◽  
Multiple Cancer ◽  
Functional Variants ◽  
Genotype Frequencies ◽  
Common Genetic Variants ◽  
Increased Risk ◽  
Synonymous Sites

Background:TERTencodes the telomerase reverse transcriptase, which is responsible for maintaining telomere ends by addition of (TTAGGG)nnucleotide repeats at the telomere.  Recent genome-wide association studies have found common genetic variants at theTERT-CLPTM1Llocus (5p15.33) associated with an increased risk of several cancers. Results:Data were acquired for 1627 variants in 1092 unrelated individuals from 14 populations within the 1000 Genomes Project.  We assessed the population genetics of the 5p15.33 region, including recombination hotspots, diversity, heterozygosity, differentiation among populations, and potential functional impacts. There were significantly lower polymorphism rates, divergence, and heterozygosity for the coding variants, particularly for non-synonymous sites, compared with non-coding and silent changes. Many of the cancer-associated SNPs had differing genotype frequencies among ancestral groups and were associated with potential regulatory changes. Conclusions:Surrogate SNPs in linkage disequilibrium with the majority of cancer-associated SNPs were functional variants with a likely role in regulation ofTERTand/orCLPTM1L. Our findings highlight several SNPs that future studies should prioritize for evaluation of functional consequences.

SYNJ2 Variant Rs9365723 is Associated with Colorectal Cancer Risk in Chinese Han Population

2016 ◽  
Vol 31 (2) ◽  
pp. 138-143 ◽  
Author(s):  
Qingguo Du ◽  
Xueyan Guo ◽  
Xiyang Zhang ◽  
Wenjing Zhou ◽  
Zhuo Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Genetic Model ◽  
Association Studies ◽  
Chinese Han Population ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Chinese Han ◽  
Han Population ◽  
Increased Risk

Purpose Colorectal cancer (CRC) is the third most common cancer and fourth leading cause of cancer mortality, and twin studies have shown that approximately 35% of the variation in susceptibility to CRC involves inherited genetic differences. We sought to investigate potential genetic associations between some single nucleotide polymorphisms (SNPs) and the risk of CRC in the Chinese Han population. Methods We conducted a case-control study including 269 cases and 309 controls. Sixteen SNPs associated with CRC risk were selected from previous genome-wide association studies and genotyped using Sequenom MassARRAY technology. Odds ratios and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusting for age and gender. Results Using the chi-squared test we found that rs9365723 was associated with CRC risk (p = 0.012). With genetic model analysis, the genotype A/G-G/G (OR = 1.50; 95% CI 1.02-2.21; p = 0.038) of rs9365723 showed an increased risk of CRC in the dominant model. Furthermore, we found that rs9365723 was associated with an increased risk only for colon cancer but not rectal cancer (p = 0.009 and p = 0.414, respectively). Conclusions Our results, combined with previous studies, suggest that rs9365723, located on SYNJ2, is associated with the risk of CRC in a Chinese population. Thus, SYNJ2 may play a role in the development of CRC, especially colon cancer.

Association of colorectal cancer susceptibility variants with tumor subtypes in three large prospective cohorts.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 445-445 ◽  
Author(s):  
Xabier Garcia-Albeniz ◽  
Hongmei Nan ◽  
Charles S. Fuchs ◽  
Edward L. Giovannucci ◽  
Jing Ma ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lower Risk ◽  
Cancer Susceptibility ◽  
Association Studies ◽  
Tumor Stage ◽  
Health Study ◽  
Genome Wide Association Studies ◽  
Case Control Studies ◽  
Tumor Subtypes ◽  
T Stage

445 Background: Genome-wide association studies (GWAS) have identified 17 colorectal cancer (CRC) susceptibility variants. However, their association with specific tumor subtypes has not been fully defined. Methods: We genotyped (TaqMan OpenArray) 17 variants (rs6691170, rs6687758, rs10936599, rs11169552, rs7136702, rs6983267, rs16892766, rs10795668, rs3802842, rs4444235, rs4779584, rs9929218, rs4939827, rs10411210, rs961253 , rs7014346 and rs2151512 as proxy of rs4925386) in three independent prospective, CRC case-control studies nested within the Nurses’ Health Study, Health Professionals Follow-up Study, and Physicians Health Study cohorts (1227 cases, 2201 age- and race-matched controls). Genotyping success: 98.1%. All variants fitted HWE (P>0.05). We assessed the association of these variants with risk of CRC using logistic regression (LR) adjusted for age, race and study under an additive model. We used multinomial LR models to examine the association of variants to CRC according to T, N and M-stage, grade of differentiation, tumor site, and age at diagnosis. Heterogeneity in the associations were evaluated by a case-case only LR model. Results: We observed associations with CRC for rs6983267 (OR 0.86, 95% CI, 0.77-0.95; p=0.0028 -T allele-), rs3802842 (OR 1.18; 95% CI, 1.05-1.31; p=0.0036 -C allele-), rs7014346 (OR 1.15, 95% CI, 1.04-1.28, p=0.0082 -A allele-), rs11169552 (OR 0.88, 95% CI 0.78-0.99 -T allele-) and rs4939827 (OR 0.90, 95%CI 0.82-1.00, p=0.0508 – C allele-). The association between rs4939827 (MAF 48.34%) and risk of CRC was significantly different according to T stage (p for heterogeneity < 0.0001). rs4939827 was associated with a lower risk of CRC with tumor stage T1 or T2 (OR, 0.72; 95% CI, 0.63-0.84, p<.0001) but not of cancers with tumor stage T3 or T4 (OR, 1.04; 95% CI, 0.92-1.19). This result is consistent within each cohort. Conclusions: Among 17 CRC susceptibility variants, we observed that the minor allele of rs4939827 was associated with a lower risk of colorectal cancers with lower T stage but not higher T stage. These results suggest that rs4939827, which codes for an intronic region of SMAD7, may be mechanistically related to tumor invasiveness.

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