48 KB118 KB46 KB192920262005Ravnik-Glavač, Metkaštevilka:7/8letnik:74str. 443-448ISSN:1318-0347COBISSID:20214489URN:URN:NBN:SI:doc-HMSWDQRZslSlovensko zdravniško društvoZdravniški vestnikColorectal Neoplasms, Hereditary Nonpolyposisdebelo črevoDiagnosisdiagnostikaGenes, DccGenes, MccGeneticsGeni DCCGeni MCCKolorektalne novotvorbe dedne, nepolipozneMicrosatellite RepeatsMikrosatelitne ponovitvemolekularna genetikanovotvorbepresejalni testirak (medicina)rektalne boleznitumorMolekularnogenetski pristop za presejanje dednega nepolipoznega kolorektalnega karcinoma| Molecular genetic approach for screening of hereditary non-polyposis colorectal cancer|Background. The main goal of knowledge concerning human diseases is to transfer as much as possible useful information into clinical applications. Hereditary non-polyposis colorectal cancer (HNPCC) is the most common autosomal dominant inherited predisposition for colorectal cancer, accounting for 1-2% of all bowel cancer. The only way to diagnose HNPCC is by a family history consistent with the disease defined by International Collaborative Group on HNPCC (Amsterdam criteria I and II). The main nolecular cause of HNPCC is a constitutional mutation in one of the mismatch repair (MMR) genes. Since HNPCC mutations have been detected also in families that did not fulfil the Amsterdam Criteria, molecular genetic characteristics of HNPCC cancers have been proposed as valuable first step in HNPCC identification. Microsatellite instability is present in about 90% of cancers of HNPCC patients. However, of all MSI colorectal cancers 80-90% are sporadic. Several molecular mechanisms have been uncovered that enable distinguishing to some extent between sporadic and HNPCC cancers with MSI including hypermethylation of hMLH1 promoter and frequent mutations in BAX and TGFBR2 in sporadic CRC with MSI-H. Conclusions. The determination of MSI status and careful separation of MSI positive colorectal cancer into sporadic MSI-L, sporadic MSI-H, and HNPCC MSI-H followed by mutation detection in MMR genes is important for prevention, screening and management of colorectal cancer. In some studies we and others have already shown that large-scale molecular genetic analysis for HNPCC can be done and is sensitive enough to approve population screening. Population screening includes also colonoscopy which is restricted only to the obligate carriers of the mutation. (Abstract truncated at 2000 characters)Izhodišča. Glavni cilj znanja o bolezni pri človeku je, prenesti čim več uporabnih informacij v klinično prakso. Dedni nepolipozni kolorektalni karcinom (HNPCC za angl. hereditary non-polyposis colorectal cancer) ali sindrom Lynch je najpogostejša avtosomno-dominantno dedovana nagnjenost za kolorektalni karcinom, ki zajema 1-2% vseh primerkov raka debelega črevesa. Osnova najpogostejšega načina za prepoznavanje sindroma HNPCC je družinska anamneza, kakor jo je opredelila Mednarodna skupina za HNPCC (Amsterdamska merila I in II). Glavni molekularni vzrok za HNPCC je podedovana mutacija v enem od genov, ki kodirajo proteine, odgovorne za popravljanje napak pri podvojevanju DNK (MMR za ang. mismatch repair). Ker so mutacije v genih MMR našli tudi pri družinah, ki niso izpolnjevale amsterdamskih meril, so predlagali, naj bi bile molekularnogenetske značilnosti sindroma HNPCC lahko prva stopnja pri prepoznavanju sindroma. Več kot 90% tumorjev bolnikov s HNPCCnamreč izraža genetsko mikrosatelitno nestabilnost. Ker pa je tudi približno 10% sporadičnih kolorektalnih karcinomov genetsko nestabilnih v predelih mikrosatelitov, je bilo potrebno razkriti molekularne mehanizme, ki ločijo mikrosatelitno nestabilne tumorje HNPCC od tumorjev sporadičnega izvora. Zdaj je znano, da so pri sporadični obliki visoko mikrosatelitno nestabilnih tumorjev pogosteje hipermetilacija v promotorju gena MLH1 ter mutacije v genih BAX in TGFBR2. Zaključki. Določitev statusa MSI in njegova ločitev na sporadične tumorje in tumorje HNPCC ter nadaljnja mutacijska analiza v tumorjih HNPCC je pomembna za presejanje in preprečevanje dednega kolorektalnega raka. (Izvleček prekinjen pri 2000 znakih)TEXTznanstveno časopisjejournalsSlovenian National E-content AggregatorNational and University Library of SloveniaSlovensko zdravniško društvo