Department of the Molecular Biology of Cancer
Colorectal cancer (CRC) is a common neoplasia in both men and women (with an estimated risk incidence of 5 % worldwide) and ranks as the fourth most common cancer in the world, with approximately 875,000 new cases diagnosed each year. An increased incidence in Europe has been recorded over the past decade, with a particularly severe situation in the central European region. The incidence of CRC in the Czech Republic ranks third worldwide, while the incidence of rectal cancer, particularly in men, is the highest. Both environmental and genetic factors are involved in the onset of sporadic CRC, which represents the predominant form of this cancer (approx. 90% of all cases). It is believed that sporadic CRC involves multiple genes with moderate effects (low penetrance type) and progression occurs due to aggressive gene-environment interactions. The complex etiology of CRC and the observed high incidence in the Czech Republic stress the importance of a systematic approach, combining epidemiological and molecular biological methods, to understand the critical pathways in CRC tumorigenesis. Our recent interest has been oriented towards chemotherapy regimes, usually selected with the help of classical predictive markers such as TNM, which are not equally effective in all patients and which exert significant side effects. An assumption that the genetic profiles of patients could improve the prediction of an individual’s response to standard chemotherapy regimes in CRC resulted in a selection of candidate genes, comprising the metabolic, transport, DNA repair and cell-cycle genes. Screening the loci in the above genes may have relevance in pharmacogenomics with the ultimate goal of individualized chemotherapy. Most recently, the participation of the Department in a multicenter study has resulted in the identification of several susceptibility loci of CRC using genome wide association (GWA). A detailedanalysis of these loci, regarding their function in tumor cell biology, is ongoing.
Laboratory of DNA Repair
Research topics
- Investigation of the mechanisms involved in DNA repair pathways;
- functional tests for DNA repair capacity;
- expression of relevant DNA repair candidate genes;
- interest in genotype-phenotype interactions;
- the role of several DNA repair path–ways in carcinogenesis.
Nuclear DNA is constantly exposed to DNA damaging agents from the environment and the diet. Normally, there is a dynamic equilibrium between DNA damage and its removal by effective and accurate cellular repair enzymes. If the steady state is disturbed, the damage measured will increase, but then increased repair activity (through normal enzyme kinetics, with possibly induction or activation in addition) will tend to restore the equilibrium. The steady state level depends on the intrinsic repair rate in the individual’s cells, which may be in part genetically determined and in part affected by metabolic or environmental factors.
