A molekuláris onkogenezis mechanizmusai gyakori daganatokban = Mechanisms of molecular oncogenesis in common malignancies

Munkacsoportunk két évtizede megkezdett kutatási programját folytatta, amelynek fő célkitűzése új molekuláris rákgenetikai ismeretek szerzése a rák iránti fokozott genetikai fogékonyság molekuláris tényezőinek megismerésére. Vizsgálataink a Magyarországon gyakori daganatos megbetegedésekre (emlőrák, vastagbélrák, ivarszervi daganatok), elsősorban ezek familiáris formáira irányultak. Folytattuk, illetve megkezdtük a daganatszindrómák hajlamosító génjeinek elemzését örökletes emlő- és petefészekrákokban (BRCA1/2, CHEK2), familiáris adenomatozus polyposisban (APC), és herediter, nem a polyposis talaján kialakuló vastagbélrák szindróma (HNPCC) "mutátor gén"-jeiben (MSH2, MLH1). Az emlőrákos családokon, valamint kohorszokon nyert kutatási eredmények adatainak nemzetközi szintű összesítése, molekuláris epidemiológiai kiértékelése révén az örökletes daganatok kialakulására hajlamosító mutációt hordozók rákkockázatáról, a prevenciós tényezőkről és a betegség genetika-klinikai-pathológiai összefüggéseiről szereztünk további új ismereteket. Nemzetközi együttműködésben hozzájárultunk a csírasejtes hererákra hajlamosító első genetikai variánsok azonosításához. Daganatos megbetegedésre hajlamosító gének (BRCA1, STK11) esetében elemeztük az alternatív splicing szerepét a betegség kialakulásában. Újabban megkezdett génexpressziós profilvizsgálatok révén bepillantást nyertünk a molekuláris genetikai útvonalak és a metabolikus útvonalak kölcsönhatásába. | We have extended our molecular cancer genetic studies that were initiated in Hungary two decades ago and were aimed at providing new knowledge on molecular cancer genetics, with a focus on genetic susceptibility to cancer. The studies were conducted on common malignancies in Hungary (breast, colorectal and genitourinary cancers). Extended analysis of the predisposing genes of cancer syndromes was initiated or continued for hereditary breast- and/or ovarian cancer (BRCA1, BRCA2, CHEK2), for familial adenomatous polyposis (APC), for Peutz-Jeghers syndrome (STK11), and for hereditary non-polyposis colorectal carcinoma, HNPCC ("mutator genes" such as MSH2, MLH1). Forwarding the result and data of our molecular genetic analysis on breast cancer families and cancer cohorts for international data integration and molecular epidemiological analysis resulted in generation of new knowledge on cancer risk for the carriers of deleterious germ-line mutations, and on genetic-clinical and pathological correlations in development of breast cancer. Participating in international studies we have contributed to identification of new genetic variants predisposing to germ cell testicular cancer. The role of alternative splicing in development of cancer was investigated in cancer susceptibility genes BRCA1 and STK11. By recent introduction of gene-expression profiling we have gained preliminary insight into the interaction of metabolic and molecular pathways

The potential impact of new generation transgenic methods on creating rabbit models of cardiac diseases

Since the creation of the first transgenic rabbit thirty years ago, pronuclear microinjection remained the single applied method and resulted in numerous important rabbit models of human diseases, including cardiac deficiencies, albeit with low efficiency. For additive transgenesis a novel transposon mediated method, e.g., the Sleeping Beauty transgenesis, increased the efficiency, and its application to create cardiac disease models is expected in the near future. The targeted genome engineering nuclease family, e.g., the zink finger nuclease (ZFN), the transcription activator-like effector nuclease (TALEN) and the newest, clustered regularly interspaced short palindromic repeats (CRISPR) with the CRISPR associated effector protein (CAS), revolutionized the non-mouse transgenesis. The latest gene-targeting technology, the CRISPR/CAS system, was proven to be efficient in rabbit to create multi-gene knockout models. In the future, the number of tailor-made rabbit models produced with one of the above mentioned methods is expected to exponentially increase and to provide adequate models of heart diseases

The potential impact of new generation transgenic methods on creating rabbit models of cardiac diseases

Since the creation of the first transgenic rabbit thirty years ago, pronuclear microinjection remained the single applied method and resulted in numerous important rabbit models of human diseases, including cardiac deficiencies, albeit with low efficiency. For additive transgenesis a novel transposon mediated method, e.g., the Sleeping Beauty transgenesis, increased the efficiency, and its application to create cardiac disease models is expected in the near future. The targeted genome engineering nuclease family, e.g., the zink finger nuclease (ZFN), the transcription activator-like effector nuclease (TALEN) and the newest, clustered regularly interspaced short palindromic repeats (CRISPR) with the CRISPR associated effector protein (CAS), revolutionized the non-mouse transgenesis. The latest gene-targeting technology, the CRISPR/CAS system, was proven to be efficient in rabbit to create multi-gene knockout models. In the future, the number of tailor-made rabbit models produced with one of the above mentioned methods is expected to exponentially increase and to provide adequate models of heart diseases