Stomach adenocarcinoma is due to non-specific symptoms often diagnosed at an advanced stage, which is the main reason for poor survival of patients. It is well established that gastric tumours are heterogeneous from the molecular standpoint and that malignant transformation of normal gastric cells is a complex and multistep process, involving different genomic, genetic and epigenetic changes. This project is based on the hypothesis that chromosomal instability (CIN) is probably an early event implicated in the initiation and development of epithelial cancers. Recent studies revealed that subtle changes in mitotic segregation genes, controlling the chromatids separation, are the most probable candidates for inducing the slow process of accumulation of genetic changes, leading to CIN. The new hypothesis is further supported by the fact that this process is slow, which explains the late onset of sporadic epithelial cancers.
Our study is based on the determination of polymorphic genes in gastric cancer patients, which could be responsible for genome instability, using genome wide association studies. Furthermore, the selected polymorphisms are evaluated in a larger cohort of patients, and the effect of polymorphisms and their combinations will be functionally assessed in controlled environment in cell lines and yeast.
The data obtained could be informative for determination of polymorphisms associated with elevated gastric cancer risk in Slovenian population. The results could be useful for the development of screening tests, biomarkers of tumour progression, and for the selecting the most appropriate therapeutic approach. There is a lack of evidence on functional effects of polymorphisms in heterologous and homologous systems; therefore the results of this study may offer a better insight in the molecular mechanisms of gastric cancer development.
⇒ Link to a current core research project: JR – SICRIS
Past and Present Research projects:
- National research program P1-0390 Functional Genomics and Biotechnology for Health; R. Komel, 1/1/2015 – 10/7/2017 / D. Rozman, 10/7/2017 – 31/12/2020 (previously P1-0104; 2009-2014, R. Komel); A/ Molecular and Cellular Understanding of Selected Complex Multifactorial Disorders: WP1b – Molecular roots of carcinogenesis (P. Hudler); http://www.sicris.si/search/prg.aspx?lang=slv&id=6087; http://www.sicris.si/search/prg.aspx?lang=slv&id=9665.
- National research project J3-5504 Role of polymorphisms in chromosome segregation genes in cancer; R. Komel, 1/8/2013 ― 31/7/2016; http://www.sicris.si/search/prj.aspx?lang=slv&id=8653.
- BI-BA/14-15-010 Characterisation of nucleotide changes (polymorphisms) in segregation and repair genes at gastric cancer: Slovenian-Bosnian Bilateral Project; R. Komel & I. Eminović, 2014-2015.
- Z3-0072 Polymorphisms and mutations in chromosome segregation genes in Slovenian gastric cancer patients; post-doctoral research project, P. Hudler, 1/2/2008 – 30/1/2010; http://www.sicris.si/search/prj.aspx?lang=slv&id=5869.
Clinical partners:
- University Clinical Centre Ljubljana (UKC), Gastroenterology Surgery Clinic (Robert Juvan, MD, MSc, Prof. Mirko Omejc, MD, PhD; Assist. Prof. Aleš Tomažič, MD, PhD)
- University Clinical Centre Ljubljana (UKC), Clinical Department for Gastroenterology (Dr. Rado Janša, MD)
Collaborating research/faculty institutes:
- Faculty of Medicine UL, Institute of Pathology
International collaboration:
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Tumour Virology, Trieste, Italy (Lawrence Banks, PhD)
- University of Sarajevo, Faculty for Mathematics and Natural Sciences, Sarajevo, BiH (Prof. Izet Eminović, PhD; Aner Mešić, PhD)
Researchers involved:
| Researcher | Position |
| Petra Hudler | Senior researcher, P. I. |
| Pia Pužar Dominkuš | Junior researcher, PhD student |
| Former Group Members | |
| Radovan Komel | MCMB leader, former contributor |
| Marija Rogar | Former PhD student |
| Aner Mešić | Former PhD student |
Education:
| Student | Thesis/Research project | Title | Year | Supervisors |
| Aner Mešić | PhD | Characterization of nucleotide changes (polymorphisms) in mitotic checkpoint genes in gastric cancer. | 2017 | Radovan Komel Izet Eminović |
| Marija Rogar | PhD | Single nucleotide polymorphisms of the chromosome segregation genes involved in the development of gastric cancer. | 2016 | Radovan Komel Petra Hudler |
| Ela Markočič | Faculty Prešern Award | Association of genetic variations in centrosomal kinases Aurora and Polo with gastric cancer susceptibility. | 2016 | Petra Hudler |
| Aida Zečkanović, Tadej Žlahtič | Faculty Prešern Award | SNP characterization in segregation genes in gastric cancer patients. | 2015 | Petra Hudler |
| Iza Ogris | BSc | Association of polymorphisms in genes BUB1B and PTTG1 with gastric cancer in a Slovenian population. | 2014 | Radovan Komel Petra Hudler |
| Nina Sodja | Student project | Selected polymorphisms in segregation genes CASC5 and ZWINT are associated with gastric cancer risk. | 2014 | Petra Hudler |
| Mateja Šimic | BSc (University programme) | TTK and BUB1B genetic polymorphisms in Slovenian gastric cancer patients. | 2012 | Radovan Komel Petra Hudler |
| Sabina Kastelic | Bsc (University programme) | Functional effects of STK15 genetic polymorphisms in Slovenian gastric cancer patients. | 2009 | Radovan Komel Petra Hudler |
Selected publications:
- Mešić A., Rogar M., Hudler P., Bilaković N., Eminović I., Komel R. (2019): Characterization of risk association of polymorphisms in Aurora kinases A, B and C with genetic susceptibility to gastric cancer development. BMC Cancer 12(1): 919 (1-14); doi: 10.1186/s12885-019-6133-z.
- Hudler P. (2018): Outlook on epigenetic therapeutic approaches for treatment of gastric cancer. Current Cancer Drug Targets 18(1): 65-88; doi: 10.2174/1568009617666170203163745.
- Mešić A. et al. (2017): Single nucleotide polymorphisms rs911160 in AURKA and rs2289590 in AURKB mitotic checkpoint genes contribute to gastric cancer susceptibility. Environmental and Molecular Mutagenesis 58(9): 701-711; doi: 10.1002/em.22129.
- Mešić A. et al. (2016): Association of the AURKA and AURKC gene polymorphisms with an increased risk of gastric cancer. IUBMB Life 68(8): 634-644; doi: 10.1002/iub.1521.
- Hudler P. et al. (2015): Association between polymorphisms in segregation genes BUB1B and TTK and gastric cancer risk. Radiology & Oncology 50(3): 297-307; doi: 10.1515/raon-2015-0047.
- Hudler P. (2015): Challenges of deciphering gastric cancer heterogeneity. Gastroenterol. 21(37): 10510-10527; doi: 10.3748/wjg.v21.i37.10510.
- Videtič Paska A., Hudler P. (2015): Aberrant methylation patterns in cancer: a clinical view. Biochemia Medica 25(2): 161-176; doi: 10.11613/BM.2015.017.
- Hudler P. (2012): Genetic aspects of gastric cancer instability. World J. 2012: 1-10; doi: 10.1100/2012/761909.
- Hudler P. et al. (2011): A genomic approach to investigate expression profiles in Slovenian patients with gastric cancer. Oncol. Lett. 2(5): 1003-1014; doi: 10.3892/ol.2011.362.