The described experimental model of clonal tumors induced through the insertional mutagenesis with MAV-2 proved to be a valid and rich source of information describing the process of transformation of normal into tumor cell. We have mapped more than 2000 individual clonal VISs from several hundreds of tumor tissue samples. We have analyzed five tumor types of different histology and tissue of origin along with their derivative tissue cultures. Furthermore, we have discovered the industasis phenomenon and described it during the course of the study. The goal of my study was to uncover common reasons for neoplastic transformation of the cell. The results of my study led me to the paradoxical conclusion that the significance of genetic changes as the primary cause of induction of neoplastic transformation is being overestimated. Although studying the functions of individual genes and search for new tumor markers and therapeutical targets are still beneficial, I believe that the traditional perception of tumor formation as a function/result of mutation accumulation and selection is becoming a serious drawback in further investigations. These conclusions are further discussed in the last section of the presented Ph.D. thesis.

Xenobiotic biotransformation process and its capacity is crucial for xenobiotic chemicals elimination that may cause damage toward cell structures. The effectiveness of the enzymes included in this process depends on the gene variants that encodes them. The aim of this work was to compare certain polymorphisms of selected genes between cases and control groups. Studied polymorphisms were null genotypes of the glutathione S-transferase gene M1 and T1 and the insertion of TA dinucleotide in the promotor region of UDP-glucuronosyl transferase 1A1. The number of cases group was six included patients with colorectal, lung, prostate, breast, pancreatic and head and neck cancer. Total number of analysed individuals was 1 118 for cancer cases and 470 for healthy controls. The control group was divided into two groups, the first one was called general and the second one was called special included healthy individuals with no cancer history in their closest family members. Gilbert syndrome (GS) is caused by homozygous insertion of the TA dinucleotide in the TATA box of the gene UGT1A1 and it causes elevated bilirubin levels. Bilirubin is a potent antioxidant in human body, so the aim was to attest its protective effect toward cancer. We expected lower frequency of GS as a protective factor in the cases groups compared with controls. This hypothesis was confirmed in the breast cancer group (GS frequency 10,0 %) and pancreatic cancer group (GS frequency 11,1 %). In the general and special control groups the frequency of GS was 16,0 % and 15,4 % respectively. Although the other case groups show lower frequency of GS, the results weren´t statistically significant. Null GSTM1 genotype was observed with 50,4 % frequency in the general control groups and with 55,3 % frequency in the special control group. Neither the one of the cases groups hasn´t showed significantly lower percentage of null genotype. Despite expectation we observed statistically significant lower frequency of null genotype in the group of lung and pancreatic cancer group (37,4 % and 39,3 % respectively). According to this study, we can say that the lack of glutathione S-transferase M1 activity is not a risk factor for cancer development. Null genotype of GSTT1 wasn´t identified in both control groups at all. In case groups of breast and prostate cancer, there was only one individual carrying the null GSTT1 genotype. Statistically significant higher frequency of this polymorphism was observed in patients with colorectal cancer (9,7 %), lung cancer (17,2 %), pancreatic cancer (3,0 %) and head and neck cancer (15,9 %). In these groups the lack of glutathion S-transferase T1 activity might be considered as risk factor for cancer development. Nevertheless, for further verification it needs to take more investigation in this field, especially enlarge the number of patient in the case groups of head and neck, lung and pancreatic cancer.

Squamous cell carcinoma is the most frequent malignant tumour of head and neck. Prognostic and predictive information as an individual imprint of molecular-genetic analysis of HNSCC will help to determine the best indivicual treatment. And in case of surgical appraoch the optimal resection with adequate quality of life and long-term survival. Study of early cancerogenesis in our project is based on knowledge, that histological normal mucosa next to tumor shows preneoplastic molecular alterations. Molecular genetic changes in a histological normal mucosa harbouring a tumor may play a principal role in revealing of early cancerogenesis process. Molecular-genetic analysis of cancerogenesis in HNSCC reveals prognostic and predictive factors, which are necessary for evaluation and decission for the best individual treatment. This is the concept of tailored medicine The text summarizes current knowledge of early cancerogenesis in HNSCC and presents molecular-biological trends, which are necessary to discover details of early cancerogenesis and thus to get a tool for better detection as well as treatment of malignant disease. The study is based on fragment analysis of microsatelites lesions in tumor tissue in comparison to adjacent mucosa and the healthy mucosa. Results show significant molecular-biological...