scholarly journals In-silico analysis of MHC genes in hereditary colorectal cancer shows identical by state SNP sharing affecting HLA-DQB1 binding groove

2016 ◽  
Author(s):  
Mahmoud Koko ◽  
Suleiman Hussein Suleiman ◽  
Mohammed Omar Elsiddieg Abdallah ◽  
Muhallab Saad ◽  
Muntaser Ibrahim
Keyword(s):  
Colorectal Cancer ◽  
In Silico ◽  
Cancer Susceptibility ◽  
Human Leukocyte ◽  
Hereditary Colorectal Cancer ◽  
The Cancer Genome Atlas ◽  
Exome Capture ◽  
Nucleotide Polymorphisms ◽  
Mhc Ii ◽  
Binding Groove

Background: The role of Human Leukocyte Antigen (HLA) alleles in colorectal cancer susceptibility, development and progression is the focus of ongoing scrutiny. MHC polymorphisms in a Sudanese family with hereditary colorectal cancer were studied using an in silico approach and the results were verified using The Cancer Genome Atlas (TCGA). In this family study, we tested for sharing of nucleotide polymorphisms identified by whole exome capture in major histocompatibility complex region and carried out in-silico prediction of their effects in tumor and control samples. SNPs were analyzed to highlight identical by state sharing, to identify runs of homozygosity, as well as to predict structural and functional effects using homology modeling, damaging effect predictions, and regulatory changes prediction. Results: MHC II area showed significantly high degree of homozygosity in tumor samples. Non-synonymous SNPs shared identical by state (IBS) between tumor samples were predicted to affect HLA-DQB1 binding groove. A similar haplotype of these SNPs was identified in a TCGA colonic adenocarcinoma tumor sample. No significant regulatory effects (in the form of transcription factor or miRNA binding site variants) were predicted. Conclusions: The results demonstrate IBS SNP sharing of markers affecting HLA-DQB1 binding specificity and probable loss of heterozygosity in MHC II region in colorectal cancer.

scholarly journals Shedding Light on the Interaction of Human Anti-Apoptotic Bcl-2 Protein with Ligands through Biophysical and in Silico Studies

2019 ◽  
Vol 20 (4) ◽  
pp. 860 ◽  
Author(s):  
Joao Ramos ◽  
Jayaraman Muthukumaran ◽  
Filipe Freire ◽  
João Paquete-Ferreira ◽  
Ana Otrelo-Cardoso ◽  
...  
Keyword(s):  
Conformational Changes ◽  
In Silico ◽  
Nucleotide Polymorphisms ◽  
Ligand Interaction ◽  
Zinc Database ◽  
In Silico Studies ◽  
Anti Cancer ◽  
Binding Groove ◽  
The Stability ◽  
Dynamics Simulations

Bcl-2 protein is involved in cell apoptosis and is considered an interesting target for anti-cancer therapy. The present study aims to understand the stability and conformational changes of Bcl-2 upon interaction with the inhibitor venetoclax, and to explore other drug-target regions. We combined biophysical and in silico approaches to understand the mechanism of ligand binding to Bcl-2. Thermal shift assay (TSA) and urea electrophoresis showed a significant increase in protein stability upon venetoclax incubation, which is corroborated by molecular docking and molecular dynamics simulations. An 18 °C shift in Bcl-2 melting temperature was observed in the TSA, corresponding to a binding affinity multiple times higher than that of any other reported Bcl-2 inhibitor. This protein-ligand interaction does not implicate alternations in protein conformation, as suggested by SAXS. Additionally, bioinformatics approaches were used to identify deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) of Bcl-2 and their impact on venetoclax binding, suggesting that venetoclax interaction is generally favored against these deleterious nsSNPs. Apart from the BH3 binding groove of Bcl-2, the flexible loop domain (FLD) also plays an important role in regulating the apoptotic process. High-throughput virtual screening (HTVS) identified 5 putative FLD inhibitors from the Zinc database, showing nanomolar affinity toward the FLD of Bcl-2.

scholarly journals Genetic Variants in the Promoter Region of miR-10b and the Risk of Breast Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Jiaping Chen ◽  
Yue Jiang ◽  
Jing Zhou ◽  
Sijun Liu ◽  
Yayun Gu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Single Nucleotide Polymorphisms ◽  
In Silico ◽  
Promoter Region ◽  
Cancer Susceptibility ◽  
Chinese Women ◽  
Close Association ◽  
Breast Cancer Susceptibility ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

Variants in microRNA genes may affect their expression by interfering with the microRNA maturation process and may substantially contribute to the risk of breast cancer. Recent studies have identified miR-10b as an interesting candidate because of its close association with the metastatic behavior of breast cancer. However, the roles of miR-10b-related single nucleotide polymorphisms in breast cancer susceptibility remain unclear. This case-control study evaluated the associations between variants in the upstream transcription regulation region of miR-10b and the risk of breast cancer among Chinese women. Seven potentially functional SNPs were investigated using genotyping assays. The potential biological functions of the identified positive SNPs were further evaluated using in silico databases. We found that rs4078756, which was located at the promoter region of miR-10b, was significantly associated with breast cancer risk (rs4078756 AG/GG versus AA, adjusted odds ratio: 1.17, 95% confidence interval: 1.02–1.35). The other six single nucleotide polymorphisms exhibited negative associations. Based on the in silico prediction, rs4078756 potentially regulated miR-10b expression through promoter activation or repression. These findings indicate that a potentially functional SNP (rs4078756) in the promoter region of miR-10b may contribute to breast cancer susceptibility among Chinese women.

scholarly journals lncRNA-PCAT1 rs2632159 polymorphism could be a biomarker for colorectal cancer susceptibility

2019 ◽  
Vol 39 (7) ◽  
Author(s):  
Ming-li Yang ◽  
Zhe Huang ◽  
Li-na Wu ◽  
Rong Wu ◽  
Han-xi Ding ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Rectal Cancer ◽  
Colon Cancer ◽  
Cancer Risk ◽  
Cancer Susceptibility ◽  
Bioinformatic Analysis ◽  
Recessive Model ◽  
Eqtl Analysis ◽  
Nucleotide Polymorphisms ◽  
Colon Cancer Risk

AbstractBackground: Single-nucleotide polymorphisms (SNPs) in lncRNAs could be biomarkers for susceptibility to colorectal cancer (CRC), but the association of PCAT1 polymorphisms and CRC susceptibility is yet to be studied. Methods: Five tagSNPs covering the PCAT1 gene were detected through Kompetitive Allele-Specific PCR among 436 CRC patients and 510 controls. An expression quantitative trait locus (eQTL) bioinformatic analysis was then performed. Results: In the present study, PCAT1 rs2632159 polymorphism increased CRC risk by 1.37-fold and 2.19-fold in the dominant and recessive models, respectively (P=0.040 and 0.041). When the CRC cases were divided into colon cancer and rectal cancer, we found that this polymorphism affected colon cancer risk under the dominant model (P=0.022, OR = 1.51) and affected rectal cancer susceptibility under the recessive model (P=0.009, OR = 3.03). A more pronounced effect was observed in the male subgroup in that PCAT1 rs2632159 SNP increased rectal cancer risk by 3.97-fold (P=0.017). When PCAT1 rs2632159 was present, epistatic effects were observed with rs1902432 and rs785005 (P=0.011 and 0.008, respectively). eQTL analysis showed that rs2632159 could influence binding with the transcription factors EBF, LUN-1, and TCF12. Conclusion:PCAT1 rs2632159 SNP could be a biomarker for CRC risk. And the rs1902432 SNP might only have potential to be a biomarker for colon cancer risk.

scholarly journals Polymorphisms of a novel long non-coding RNA RP11-108K3.2 with colorectal cancer susceptibility and their effects on its expression

2019 ◽  
Vol 35 (1) ◽  
pp. 3-9
Author(s):  
Danjie Jiang ◽  
Mingjuan Jin ◽  
Ding Ye ◽  
Yingjun Li ◽  
Fangyuan Jing ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Susceptibility ◽  
Nucleotide Polymorphisms ◽  
Coding Region ◽  
Chinese Populations ◽  
Lncrna Transcript ◽  
Validated Questionnaire ◽  
Non Coding Rna ◽  
Validation Set ◽  
Long Non Coding Rna

Background: RP11-108K3.2 was recently identified as a novel long non-coding RNA (lncRNA) transcript, and several single nucleotide polymorphisms (SNPs) have been identified in its coding region. This study aimed to explore the associations of tagSNPs in RP11-108K3.2 with the risk of colorectal cancer and their effects on its expression. Methods: A total of 821 colorectal cancer cases and 857 healthy controls were enrolled into this two-stage case-control study. Demographic characteristics and lifestyle information were collected by a validated questionnaire. Six tagSNPs were genotyped by using Sequenom MassARRAY platform. A total of 71 additional colorectal cancer cases were recruited, of which the genotypes of potential polymorphisms and the RP11-108K3.2 expression levels were determined. Results: In the discovery set, only the rs2470151 C/T polymorphism was found to have a promising association with the risk of colorectal cancer, and this polymorphism was further replicated in the validation set with a significantly decreased risk of colorectal cancer (adjusted odds ratio 0.73; 95% confidence interval 0.55, 0.97). Combined discovery set and validation set together, this negative association was found both in the heterozygote codominant model and the dominant model. Furthermore, colorectal cancer patients carrying rs2470151 CT/TT genotypes had a marginally lower RNA expression of RP11-108K3.2 than those carrying the CC genotype. Stratified analyses showed the association between rs2470151 and the risk of colorectal cancer were influenced by family history of cancer, smoking, alcohol consumption, and tea drinking. Conclusions: These findings suggest that RP11-108K3.2 rs2470151 had a significant association with the risk of colorectal cancer; this may help to predict the susceptibility of colorectal cancer in Chinese populations.

scholarly journals Association analysis of miRNA-related genetic polymorphisms in miR-143/145 and KRAS  with colorectal cancer susceptibility and survival

2021 ◽  
Author(s):  
Danyang Wang ◽  
Qingmin Liu ◽  
Yanjun Ren ◽  
Yan Zhang ◽  
Xin Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Genetic Polymorphisms ◽  
Target Gene ◽  
Cancer Susceptibility ◽  
Gene Interaction ◽  
Tertiary Hospital ◽  
Cancer Tissue ◽  
Nucleotide Polymorphisms ◽  
Aberrant Expression ◽  
Genomic Regions

Background There is accumulating evidence of aberrant expression of miR-143 and miR-145 and their target gene KRAS in colorectal cancer (CRC). We hypothesize that single nucleotide polymorphisms (SNPs) within or near mRNA-miRNA binding sites may affect miRNA/target gene interaction, resulting in differential mRNA/protein expression and promoting the development and progression of CRC. Methods We conducted a case-control study of 507 patients with CRC recruited from a tertiary hospital and 497 population-based controls to assess the association of genetic polymorphisms in miR-143/145 and the KRAS 3′untranslated region (3′UTR) with susceptibility to CRC and patients’ survival. In addition, genetic variations of genomic regions located from 500 bp upstream to 500 bp downstream of the miR-143/miR-145 gene and the 3′UTR of KRAS were selected for analysis using the Haploview and HaploReg software. Results Using publicly available expression profiling data, we found that miR-143/145 and KRAS expression were all reduced in rectal cancer tissue compared to adjacent non-neoplastic large intestinal mucosa. The rs74693964 C/T variant located 65 bp downstream of miR-145 genomic regions was observed to be associated with susceptibility to CRC (adjusted odds ratio 2.414, 95% CI: 1.385–4.206). Cumulative effects of miR-143 and miR-145 on CRC risk were observed (Ptrend=0.03). Patients having CRC carrying variant genotype TT of KRAS rs712 had poorer survival (log-rank P=0.044, adjusted hazard ratio 4.328, 95% CI: 1.236–15.147). Conclusions Our results indicate that miRNA-related polymorphisms in miR-143/145 and KRAS are likely to be deleterious and represent potential biomarkers for susceptibility to CRC and  patients’ survival.

Polymorphisms of the Highly Expressed IL-6 Gene in the Papillary Thyroid Cancer Susceptibility Among Chinese

2019 ◽  
Vol 19 (6) ◽  
pp. 443-451 ◽  
Author(s):  
Honghui Li ◽  
Hao Dai ◽  
Huajing Li ◽  
Baiya Li ◽  
Yuan Shao
Keyword(s):  
Risk Factor ◽  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Cancer Susceptibility ◽  
Additive Model ◽  
In Silico Analysis ◽  
The Cancer Genome Atlas ◽  
Dominant Model ◽  
Nucleotide Polymorphisms ◽  
Papillary Thyroid

Background: Papillary thyroid cancer (PTC) is the cardinal histologic type of thyroid cancer, which is the most prevalent kind of endocrine malignancy. The expression of IL-6 is found higher in thyroid carcinoma (THCA) samples than paired normal tissues based on The Cancer Genome Atlas (TCGA) and Genotype-Tissue expression (GTEx) database. In this study, we aimed to investigate the association between interleukin-6 (IL-6) polymorphisms and the PTC risk. Methods: A case-control study was designed using the following data: 241 PTC patients and 463 healthy controls. Five single nucleotide polymorphisms (SNPs) in IL-6 were selected and genotyped using Agena MassARRAY technology. Results: Our results revealed that SNP rs1800796 was associated with an increased PTC risk in co-dominant model (p = 0.042) and dominant model (p = 0.027). Rs1524107 was also a risk factor for PTC susceptibility in co-dominant model (p = 0.003), dominant model (p = 0.002) and log-additive model (p = 0.044). Moreover, rs2066992 significantly increased the PTC risk in co-dominant model and dominant model (p = 0.011, p = 0.009, respectively). Additionally, rs2069837 variant elevated the PTC risk based on dominant model (p = 0.041). In silico analysis, GTEx results for rs1800796, rs1524107 and rs2066992 variants are known to be associated with IL-6 gene expression. Using HaploReg, we found rs1800796, rs1524107 and rs2066992 in LD with functional importance. Conclusion: Our study indicates that IL-6 variants may be a risk factor involved in the pathogenesis and development of PTC.

scholarly journals Four novel polymorphisms in long non-coding RNA HOTTIP are associated with the risk and prognosis of colorectal cancer

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Zhi Lv ◽  
Qian Xu ◽  
Liping Sun ◽  
Jing Wen ◽  
Xinxin Fang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Susceptibility ◽  
Human Cancer ◽  
Predictive Biomarkers ◽  
Nucleotide Polymorphisms ◽  
Specific Pcr ◽  
Non Coding Rna ◽  
And Function ◽  
Stratified Analysis ◽  
Long Non Coding Rna

AbstractBackground: The role of long non-coding RNA (lncRNA) HOXA transcript at the distal tip (HOTTIP) as an oncogene in varieties of human cancer including colorectal cancer (CRC) has been extensively researched. The expression and function of lncRNAs could be affected by single nucleotide polymorphisms (SNPs), which are associated with cancer susceptibility and prognosis. However, no investigation has focused on the association between HOTTIP SNPs and CRC. The aim of the present study was to explore the association of polymorphisms in the lncRNA HOTTIP gene with CRC risk and prognosis. Methods: A total of 1848 subjects were enrolled in our study, including 884 CRC cases and 964 controls. Genotyping for five HOTTIP tagSNPs (rs3807598, rs17501292, rs2067087, rs17427960, and rs78248039) was performed by applying Kompetitive allele specific PCR (KASP). Results: The results showed three SNPs (rs3807598, rs2067087, and rs17427960) were associated with enhanced CRC risk both in overall and stratified analysis. One polymorphism, rs17501292, could improve the overall survival (OS) of CRC patients in the tumor of ulcerative/invasive-type subgroup. Conclusion: These findings suggest HOTTIP SNPs could potentially be predictive biomarkers for CRC risk and prognosis. The present study provides clues for further exploration of novel lncRNA-based genetic biomarkers to predict CRC susceptibility as well as clinical outcome.

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