Molecular genetics and pharmacogenetics of gastrointestinal tumors
Colorectal adenocarcinoma is one of the most common cancers and the second leading cause of cancer in the Western world. The most cases of colon cancer occur in sporadic form while the hereditary factors are considered to be the cause of up to 20% of colon cancers. Until today the best defined hereditary syndromes are familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC). FAP is dominantly inherited disease caused by inherited mutations in theAPCgene. Another type of polyposis that must be distingiushed from FAP is MYH polyposis. This autosomal-recessive hereditary disease is associated with biallelic inherited mutations of MYH gene. The genetic basis for HNPCC us a germ-line mutation of the mismatch repair (MMR) genes.Formation of new blood vessels (neoangiogenesis) at the tumor site is required for expansion of the tumour at the point on which diffusion of nutrients and waste products become rate limiting for continued development of the tumour. Tumour angiogenesis results from a cascade of molecular and cellular events and is initiated by pro-angiogenic stimuli, which include acidic pH, cytokines, growth factors, activation of oncogenes or hypoxia. Angiogenesis is dependent on the balance between stimulatory and inhibitory factors. The change from prevascular to vascular phase, the key event for the progression and metastasis of tumors, is known as the angiogenic “switch”. With the complete sequence of the human genome available, individualized medicine may soon become reality. Genomic information may allow more accurate prediction of an individual's drug response and selection of the appropriate drug dosage to achieve the optimal therapeutic respons, avoid therapeutic failure, and minimize side effects and toxicity. Clinical use of pharmacogenetic testing has been severely limited by a lack of prospective clinical trials. Such trials are required to establish that pharmacogenetic testing benefits the selection of the appropriate drug and dose for the individual patient, thereby improving therapeutic responses and/or reducing ADRs.The main goal of this study is to investigate hereditary and sporadic genetic changes in benign and malignant gastrointestinal tumors in order to elucidate the mechanisms of their development and progression. The results of this study will offer more efficient presymptomatic diagnostics of germ-line mutations carriers in our population. Imbalanced expression of pro- and antiangiogenic factors and their receptors is the key event for the progression and metastasis of tumors and some of these factors will be addressed in our study as well. The goal of this investigation is also to start with prospective pharmacogenetic study to examine the correlation between known polymorpisms and gastrointestinal cancer therapy in the patients in Croatian population.