http___www.irb.hr_Istrazivanja_Zavodi_Zavod-za-molekularnu-medicinu_Laboratorij-za-personaliziranu-medicinu_Molekularna-genetika-i-farmakogenetika-gastrointestinalnih-tumora_1.xml
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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. - Project leader / principal investigator - Associates Tina Catela Ivković, B. Tamara Čačev, Ph.D. Marija Gamulin, Ph.D. Mladen Jokić, Ph.D. Šimun Križanac, Ph.D. Senka Radošević, M. Maja Sirotković-Skerlev, Ph.D.
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Molekularna genetika i farmakogenetika gastrointestinalnih tumora Karcinom debelog crijeva jedan je od najčešćih zloćudnih tumora i drugi po redu uzrok smrti od raka u razvijenim zemljama. Većina karcinoma debelog crijeva posljedica je stupnjevitog procesa tijekom kojeg iz dobroćudnog adenoma kao posljedica naslijeđenih i/ili stečenih mutacija nastaje zloćudni invazivni tumor. Najbolje definirani nasljedni sindromi su obiteljska adenomatozna polipoza (FAP) i nasljedni nepolipozni karcinom debelog crijeva (HNPCC). FAP je autosomno dominantno nasljedno oboljenje koje se javlja kao posljedica nasljedne mutacije u tumor supresorskom genu APC. U novije vrijeme opisana je i autosomno recesivno nasljedna polipoza čovjeka koja se javlja kap posljedica nasljednih mutacija u genu MYH. Genetska podloga sindroma HNPCC je nasljedna mutacija u jednom od gena za popravak krivo sparenih baza u DNA. Stvaranje novih krvnih žila u tumoru neophodno je za rast tumora iznad veličine pri kojoj difuzija hranjivih tvari postaje ograničavajući čimbenik. Prijelaz iz prevaskularne u vaskularnu fazu, do kojeg dolazi zbog neravnoteže stimulativnih i inhibitornih čimbenika, ključni je događaj za napredovanje i metastaziranje tumora. Podaci dobiveni analizom genoma pojedinca mogli bi omogućiti precizniji odabir terapije kako bi se postigao što bolji učinak liječenja uz što manje nepoželjnih i toksičnih nuspojava. Kako bi farmakogenetika ušla u svakodnevnu praksu potrebno je provesti prospektivna farmakogenetska testiranja kojima bi se ispitala povezanost pojedinih genskih lokusa s odgovorom na terapiju u ispitivanoj populaciji. Cilj ovog istraživanja je ispitati nasljedne i sporadične genetske promjene u gastrointestinalnim tumorima radi boljeg razumijevanja mehanizama njihovog nastanka i napredovanja. Rezultati ovog istraživanja naći će također direktnu primjenu u dijagnostici i praćenju oboljelih od nasljednih oblika gastrointestinalnih tumora. Neravnoteža pro- i anti-angiogenetskih čimbenika dovodi do pokretanja procesa stvaranja novih krvnih žila u tumoru. U našem istraživanju fokusirati ćemo se na neke od ovih čimbenika s ciljem produbljivanja spoznaja o njihovoj ulozi u procesu neoangiogeneze u gastroinestinalnim tumorima. Cilj ovog istraživanja je uspostaviti prospektivnu farmakogenetičku studiju kojom bi se ispitala korelacija između poznatih polimorfnih biljega i terapije gastrointestinalnih karcinoma. Ovi rezultati bi u konačnici trebali doprinjeti učinkovitosti terapije gastrointestinalnih tumora. - Glavni istraživač / voditelj - Ostali suradnici Dipl. ing. Tina Catela Ivković Dr.sc. Tamara Čačev Dr.sc. Marija Gamulin Dr.sc. Mladen Jokić Dr.sc. Šimun Križanac Mr.sc. Senka Radošević Dr.sc. Maja Sirotković-Skerlev