Single nucleotide polymorphisms (SNPs) in mitotic checkpoint genes can contribute to susceptibility of human cancer, including gastric cancer (GC). We aimed to investigate the effects of Aurora kinase A (AURKA), Aurora kinase B (AURKB), and Aurora kinase C (AURKC) gene polymorphisms on GC risk in Slovenian population. We genotyped four SNPs in AURKA (rs2273535 and rs1047972), AURKB (rs2241909), and AURKC (rs758099) in a total of 128 GC patients and 372 healthy controls using TaqMan allelic discrimination assays to evaluate their effects on GC risk. Our results showed that genotype frequencies between cases and controls were significantly different for rs1047972 and rs758099 (P ( 0.05). Our study demonstrated that AURKA rs1047972 TT and (CC + CT) genotypes were significantly associated with an increased risk of gastric cancer. Our results additionally revealed that AURKC rs758099 TT and (CC + CT) genotypes were also associated with increased GC risk. In stratified analysis, genotypes TT and (CC + CT) of AURKA rs1047972 SNP were associated with increased risk of both, intestinal and diffuse, types of GC. In addition, AURKC rs758099 TT and (CC + CT) genotypes were positively associated with increased intestinal type GC risk, but not with an increased diffuse type GC risk. Based on these results, we can conclude that AURKA rs1047972 and AURKC rs758099 polymorphisms could affect the risk of GC development. We proposed further larger studies to strenghten the relevance of these findings. This initiative was partly realized by ourselves: (a) in the continuation of the study on the same population we investigated the role of 6 new polymorphisms in other genes of chromosome segregation during mitosis; and (b) the entire survey was expanded to a population of patients and controls from Bosnia and Herzegovina. For the above findings, we got the confirmation of their broader force, and we have identified new genetic polymorphisms significantly associated with gastric cancer. The results of both studies are summarized in two new articles, which are in the process of submission for publication (not shown here).
COBISS.SI-ID: 32678617
Research article. Introduction: Gastric cancer is a common type of cancer; however the etiology of this heterogeneous disease is quite unknown. Carcinogenesis is very complex process involving genetic and epigenetic mechanisms. The main theme of novel genetic studies of gastric cancer is genomic instability which is broadly classified into microsatellite instability (MIN) and chromosomal instability (CIN) leading to aneuploidy. Kinases play pivotal roles throughout cellular division. From DNA damage and spindle assembly checkpoints before entering mitosis, to kinetochore and centrosome maturation and separation, to regulating the timing of entrance and exit of mitosis, mitotic kinases are essential for cellular integrity. Polymorphisms in genes which encode the mitotic kinases and/or their combinations may confer a higher relative contribution to the risk of developing cancer, but their lower penetrance makes identification more difficult. Aim: We would like to determine the association of polymorphisms and gastric cancer risk. There is a critical lack of information on the genetic backgrounds of cancer patients in Slovenia. We wish to continue and expand our pilot studies on the effect of polymorphisms in segregation genes in gastric cancer patients. Methods: We conducted a case-control study. The study included 164 patients with gastric cancer, which we collected in collaboration with the Department of Abdominal Surgery and the Department of Thoracic Surgery, University Medical Centre Ljubljana and Institute of Oncology Ljubljana. We used bioinformatics web tools in order to identify candidate SNPs in selected segregation genes, such as ZW10, CASC5, ESPL1 and TPX2. We performed SNP genotyping with TaqMan SNP assays. Results and conclusion: We found statistically significance between the tumor and the control group in polymorphism rs1185333 on the gene CASC5 (p = 0,022). According to our results we assume, that the polymorphism rs1185333 could have an impact on the development of gastric cancer. Interestingly, rs1185333 is statistically significant only in male population. Polymorphisms related to gastric cancer may be useful as potential biomarkers which could be used for detection of gastric cancer in early stages and could thus improve the prognosis of patients suffering from this type of cancer.
COBISS.SI-ID: 32403417
Gastric cancer is in decline in most developed countries; however, it still accounts for a notable fraction of global mortality and morbidity related to cancer. High-throughput methods are rapidly changing our view and understanding of the molecular basis of gastric carcinogenesis. Today, it is widely accepted that the molecular complexity and heterogeneity, both inter- and intra-tumour, of gastric adenocarcinomas present significant obstacles in elucidating specific biomarkers for early detection of the disease. Although genome-wide sequencing and gene expression studies have revealed the intricate nature of the molecular changes that occur in tumour landscapes, the collected data and results are complex and sometimes contradictory. Several aberrant molecules have already been tested in clinical trials, although their diagnostic and prognostic utilities have not been confirmed thus far. The gold standard for the detection of sporadic gastric cancer is still the gastric endoscopy, which is considered invasive. In addition, genome-wide association studies have confirmed that genetic variations are important contributors to increased cancer risk and could participate in the initiation of malignant transformation. This hypothesis could in part explain the late onset of sporadic gastric cancers. The elaborate interplay of polymorphic low penetrance genes and lifestyle and environmental risk factors requires additional research to decipher their relative impacts on tumorigenesis. The purpose of this article is to present details of the molecular heterogeneity of sporadic gastric cancers at the DNA, RNA, and proteome levels and to discuss issues relevant to the translation of basic research data to clinically valuable tools. The focus of this work is the identification of relevant molecular changes that could be detected non-invasively.
COBISS.SI-ID: 32232921
Epigenetic mechanisms, such as DNA methylation, DNA hydroxymethylation, post-translational modifications (PTMs) of histone proteins affecting nucleosome remodelling, and regulation by small and large non-coding RNAs (ncRNAs) work in concert with cis and trans acting elements to drive appropriate gene expression. Advances in detection methods and development of dedicated platforms and methylation arrays resulted in an explo - sion of information on aberrantly methylated sequences linking deviations in epigenetic landscape with the initiation and progression of complex diseases. Here, we consider how DNA methylation changes in malignancies, such as breast, pancreatic, colorectal, and gastric cancer could be explo - ited for the purpose of developing specific diagnostic tools. DNA methylation changes can be applicable as biomarkers for detection of malignant disease in easily accessible tissues. Methylation signatures are already proving to be an important marker for determination of drug sensitivity. Even more, promoter methylation patterns of some genes, such as MGMT, SHOX2 , and SEPT9 , have already been translated into commercial clinical assays aiding in patient assessment as adjunct diagnostic tools. In conclusion, the changes in DNA methylation patterns in tumour cells are slowly gaining entrance into routine diagnostic tests as promising biomarkers and as potential therapeutic targets.
COBISS.SI-ID: 32016857
Novel proteomic methods are revealing the intricacy of the epigenetic landscape affecting gene regulation and improving our knowledge of the pathogenesis of complex diseases. Despite the enormous amount of data regarding epigenetic modifications present in DNA and histones, deciphering their biological relevance in the context of the disease and health is currently still an ongoing process. Here, we consider the relationship between epigenetic research in tumorigenesis and the prospect of knowledge transfer to clinical use, focusing primarily on the epigenetic histone post-translational modifications, which could be used as biomarkers. We additionally focus on the use of proteomic techniques in research and evaluate their usefulness in clinical setting.
COBISS.SI-ID: 31865305