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The aim of this study was to evaluate changes in prognostic risk profiles of women with endometrial cancer by comparing the clinical risk assessment with the integrated molecular risk assessment profiling.

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

Colorectal cancer (CRC) represents one of the most common malignancies worldwide. Research has indicated that functional gene changes such as single nucleotide polymorphism (SNP) influence carcinogenesis and metastasis and might have an influence on disease relapse. The aim of our study was to evaluate the role of SNPs in selected genes as prognostic markers in resectable CRC.

The aim of this study was to evaluate changes in prognostic risk profiles of women with endometrial cancer by comparing the clinical risk assessment with the integrated molecular risk assessment profiling. This prospective study recruited patients with biopsy proven endometrial cancer treated at the University Medical Centre Maribor between January 2020 to February 2021. Patient clinical data was assessed and categorized according to the currently valid European Society of Gynaecological Oncology, European SocieTy for Radiotherapy and Oncology, and European Society of Pathology (ESGO/ESTRO/ESP) guidelines on endometrial cancer. Molecular tumour characterization included determination of exonuclease domain of DNA polymerase-epsilon (POLE) mutational status by Sanger sequencing and imunohistochemical specimen evaluation on the presence of mismatch repair deficiencies (MMRd) and p53 abnormalities (p53abn). Fourty-five women were included in the study. Twenty-two tumours were of non-specific mutational profile (NSMP) (56.4%), 13 were classified as MMRd (33.3%), 3 were classified as p53abn (7.7%) and 1 was classified as POLE mutated (2.6%). Six tumours (15.4%) had multiple molecular classifiers, these were studied separately and were not included in the risk assessment. The clinical risk-assessment classified 21 women (53.8%) as low-risk, 5 women (12.8%) as intermediate risk, 2 women as high-intermediate risk (5.1%), 10 women (25.6%) as high risk and 1 patient as advanced metastatic (2.6%). The integrated molecular classification changed risk for 4 women (10.3%). Integrated molecular risk improves personalized risk assessment in endometrial cancer and could potentially improve therapeutic precision. Further molecular stratification with biomarkers is especially needed in the NSMP group to improve personalized risk-assessment. [ABSTRACT FROM AUTHOR]

We have evaluated functional polymorphism (rs3087243; in literature known also as CTLA4 CT60) in the cytotoxic T lymphocyte antigen 4 (CTLA4) gene, previously associated with several autoimmune diseases, for potential association with inflammatory bowel diseases (IBD). In addition, we investigated correlations between CTLA4 CT60 polymorphism and CTLA4 gene expression in peripheral blood lymphocytes and colon biopsies from IBD patients. We genotyped CTLA4 CT60 polymorphism in 266 healthy control subjects and 481 IBD patients and found statistically lower frequency of CTLA4 CT60 AA genotype in IBD patients (13.72%) compared to control subjects (23.31%; p = 0.001, odds ratio [OR] = 0.504) as well as lower allele frequency of minor A allele in IBD patients (0.346) compared to control subjects (0.461, p < 0.001, OR = 0.623). The association was confirmed with both major forms of IBD, Crohn's disease, and ulcerative colitis (UC), but was slightly stronger in UC patients, particularly when we compared allele frequency of A allele in UC patients (0.299) and control subjects (0.461, p < 0.001, OR = 0.500). We found lower expression of the CTLA4 gene in blood lymphocytes from IBD patients compared to control subjects (p < 0.001) and higher CTLA4 expression in biopsies taken from inflamed part of the colon compared to noninflamed part of the colon (p = 0.021). We found lower expression of soluble CTLA4 isoform than membrane-bound full-length isoform in peripheral blood lymphocytes from IBD patients compared to control subjects (p = 0.010) and in lymphocytes from IBD patients with CTLA4 CT60 GG genotype compared to IBD patients with AA genotype (p = 0.034). Our genotype and gene expression data suggest that CTLA4 plays a role in IBD pathogenesis. Polymorphism CTLA4 CT60 contributes to genetic susceptibility to IBD in Slovenian population and regulates expression of CTLA4 isoforms.

Background: Asthma is one of the most common chronic diseases of childhood and results from the interaction of several genes and environmental influences. Interleukin 4 (IL4) and its receptor IL4R have a central role in the regulation of immunoglobulin E (IgE) production and thereby in the induction and maintenance of allergy and asthma. The single nucleotide polymorphisms (SNPs) Q551R in the IL4RA gene and C-33T in the IL4 gene probably influence IL4/IL4R pathway signaling; however, findings in association studies exploring the role of these two genes in asthma pathogenesis are contradictory. We have studied the association of IL4RA Q551R and IL4 C-33T SNPs with asthma, asthma phenotypes, and clinical and laboratory parameters., Methods: The study group comprised 106 children aged between 5 and 18 years with mild or moderate persistent asthma: 78 children were atopic and 28 had nonatopic asthma. The children underwent allergy and spirometry tests, a bronchoprovocation test with methacholine, measurement of exhaled nitric oxide in expired air and genotyping for IL4RA Q551R and IL4 C-33T SNPs. Genotype data from 89 nonatopic nonasthmatics served as a control group., Results: The frequency of the IL4RA Arg551 allele in the children with nonatopic asthma was 7.1%, significantly lower than 21.9% in the control group (P = 0.01, OR: 0.33, 95% CI: 0.12-0.87). Allelic and genotype frequencies in IL4 C-33T polymorphism in the asthma group and the control group were not significantly different. The mean value of total IgE in asthmatics with the IL4-33C allele was 556.0 IU/l, significantly higher than 371.6 IU/l in those with the T allele (P = 0.02). In an interaction study we did not find significant differences in the frequencies of any combinations of IL4RA Q551R and IL4 C-33T alleles between asthmatics and controls., Conclusions: The IL4RA Q551R SNP is associated with nonatopic asthma in Slovenian children. This finding contributes to knowledge about an important asthma phenotype pathogenesis and could serve in future research into new strategies for asthma management.

We genotyped CTLA4 CT60 (rs3087243) functional single nucleotide polymorphism (SNP) in children with asthma and in healthy controls and correlated the genotype data with asthma clinical data, including treatment response with inhaled corticosteroids measured by forced expiratory volume in the first second (FEV(1)). FEV(1) increased by 21.7% after 4 weeks of therapy in atopic asthmatics with the A/A genotype compared with an 8.6% increase in heterozygotes and a 5.8% increase in G/G homozygotes (p <0.01). Genotype and allele frequencies in asthmatics did not differ significantly from those in the control group. SNP CT60 in the CTLA4 gene is significantly associated with the response to treatment with inhaled corticosteroids in children with atopic asthma and could be a useful biomarker for personalized therapy in asthmatic children. SNP CT60 in the CTLA4 gene plays only a minor role in genetic susceptibility to childhood asthma in the Caucasian population.

Asthma is one of the most common chronic diseases of childhood. Asthma results from the interaction of several genes and environmental influences. Viral infections are common triggers of asthma attacks, especially in nonatopic asthmatics. CCR5 is a chemokine receptor involved in the immune response against a number of viruses. A 32 base pair deletion (delta32) in the CCR5 receptor gene causes loss of gene function and is associated with several chronic diseases due to the resulting altered immunity. The results of the association studies exploring the role of the CCR5 receptor gene in asthma pathogenesis are contradictory. We studied 111 children aged between 5 and 18 years with mild or moderate persistent asthma; 75 of them were atopic and 36 had nonatopic asthma. We carried out allergy and spirometry tests, a bronchoprovocation test with methacholine and performed measurement of exhaled nitric oxide and genotyping for CCR5-delta32 mutation. Compared with 365 nonatopic, nonasthmatic controls we found significantly lower CCR5-delta32 allelic frequency in nonatopic asthmatics (p = 0.016, OR 0.139, 95% CI 0.02 to 0.984) but not in atopic asthmatics. CCR5-delta32 mutation protects against nonatopic asthma. This association offers new insights into the pathogenesis of an important asthma phenotype and could serve as useful information for the future research of new asthma management strategies.

We have systematically retrieved genes with coding mononucleotide repeats from sequence databases and analyzed them for mutations in tumors with high levels of microsatellite instability (MSI-H). We found somatic frameshift mutations in 7/13 genes previously not analyzed in MSI-H tumors. According to the frequency of mutations in MSI-H tumors, these genes could be divided into genes with high coding mononucleotide repeat instability (CMRI-H) and genes with low coding mononucleotide instability (CMRI-L). CMR-H genes were mutated in more than 9/38 and CMRI-L in less than 4/38 of MSI-H tumors. Four genes in our study were CMRI-H and could thus possibly play a role in the development of MSI-H tumors: TFE3 (9/38), TEF4 (12/38), RGS12 (11/38), and TCF1 (12/38). Our results suggest that systematic identification of genes with CMR in the sequence databases and determination of mutation frequency in MSI-H tumors might be a powerful tool for identification of new molecular targets in the development of MSI-H tumors., (Copyright 2002 Wiley-Liss, Inc.)

We have studied 57 different mutations within three beta-globin gene promoter fragments with sizes 52 bp, 77 bp, and 193 bp by fluorescent capillary electrophoresis CE-SSCP analysis. For each mutation and wild type, energetically most-favorable predicted secondary structures were calculated for sense and antisense strands using the MFOLD DNA-folding algorithm in order to investigate if any correlation exists between predicted DNA structures and actual CE migration time shifts. The overall CE-SSCP detection rate was 100% for all mutations in three studied DNA fragments. For shorter 52 bp and 77 bp DNA fragments we obtained a positive correlation between the migration time shifts and difference in free energy values of predicted secondary structures at all temperatures. For longer 193 bp beta-globin gene fragments with 46 mutations MFOLD predicted different secondary structures for 89% of mutated strands at 25 degrees C and 40 degrees C. However, the magnitude of the mobility shifts did not necessarily correlate with their secondary structures and free energy values except for the sense strand at 40 degrees C where this correlation was statistically significant (r = 0.312, p = 0.033). Results of this study provided more direct insight into the mechanism of CE-SSCP and showed that MFOLD prediction could be helpful in making decisions about the running temperatures and in prediction of CE-SSCP data patterns, especially for shorter (50-100 bp) DNA fragments., (Copyright 2002 Wiley-Liss, Inc.)

The multidrug resistance 1 (MDRI) gene and transcription factor 4(TCF4) gene are suggested to be involved in the WNT signalling pathway, the most important pathway altered in colorectal cancer. Mutations in both genes have been identified and associated with colorectal tumors exhibiting high microsatellite instability (MSI-H). In this study, we report on the distribution of functional polymorphisms in the MDR] gene and somatic frameshift mutations in the TCF4 gene coding mononucleotide repetition in 62 MSI-H colorectal tumors. Somatic frameshift mutations in(of) the TCF4 gene were identified in 24/62 (39%) of the studied MSI-H tumors. The estimated allele frequencies of functional polymorphisms in(of) exon 21 (2677 G>T, Ala893Ser) and exon 26(3435 C>T, Ilel 142I1e) of the MDR] gene were 0.42 and 0.46 in the controls and 0.54 (p=0.035) and 0.60 (p=0.017) in the MSI-H tumors. However, the allele frequency of both functional MDR] polymorphisms did not significantly differ between MSI-H tumors with TCF4 mutations and those without. These results support the involvement of the MDRI gene in the tumorgenesis of MSI-H tumors and also suggest that functional polymorphisms in the MDRI gene and mutations in the TCF4 gene are likely to occur independently in MSI-H tumors.