Alteracions de la VIA RAS-RAF en càncer gastrointestinal amb defectes de reparació genòmica

摘要: La via Ras-Raf-MAPK regula funcions cellulars com la proliferacio, transformacio o lapoptosi. En cancer sol presentar mutacions activants en algun dels tres gens que codifiquen per a Ras (KRAS, HRAS y NRAS) i un Raf (BRAF). A mes, les de son events alternatius ja mai es donen vegada mateix tumor, suggerint aquestes activen mateixa via. colorectal (CCR) mutacio puntual BRAF V600E sassocia significativament als casos presenten inestabilitat microsatellits (MSI) solen insercio delecio sequencies repetitives. En aquesta tesi hem volgut determinar possibles associacions moleculars clinico-patologiques permetin explicar lalta capacitat tumorogenica daquesta aquest tipus especific tumor. Aixi, gastric, MSI presenta patro mutacional molt semblant al colorectal, no detectat BRAF, ni estables (MSS) MSI, mentre si confirmat lassociacio CCR. Sorprenentment, KRAS gastric tambe sassocien CCR troben ambdos fenotips (MSS MSI). Per altre costat, esporadic, estar provocat lhipermetilacio del gen MLH1, trobat cap associacio BRAF-V600E amb KRAS, APC p53. canvi, una clara MLH1. analitzant els mateixos tumors metilacio p16, p14, RASSF1A, APC, MGMT THBS1 associat MLH1 estat dhipermetilacio genomica. Duna altra banda, caracteristica clinico-patologica excepcio localitzacio detecta proximals. Tambe analitzat pacients HNPCC, tenen germinals enlloc metilacio. No aquests tumors, tant MSH2 MSH6 coneguda pero compleixen criteris clinics dAmsterdam Bethesda mes estrictes. Aixo confirma dona especificament sino hipermetilacio tenir genomica resta tumors. Apart, MSS, esporadics sense HNPCC. frequencia alta hi ha independentment seu origen esporadic hereditari. obstant, afecten sobretot codo 12 hereditaris 13 equitativament. HNPCC menor germinal te lloc MSH6. Finalment, diferencies mutacionals hereditari suggereixen modulacio diferent aixi possible activacio daltres vies alternatives depenent lestat trobi el fons genetic epigenetic labsencia total converteix eina fiable, rapida baix cost diagnostic molecular criteri dexclusio familiar. " SUMMARY: The pathway regulates functions such as cell proliferation, transformation and apoptosis. In activating mutations are present in the three genes one gene Moreover, hardly ever found together same tumor suggesting that they activate pathway. (CRC) hotspot mutation is associated to microsatellite instability (MSI), which characterised by insertion/deletion repetitive sequences. Here we have determined or clinico-pathological associations of understand its higher tumorogenic capabilities this subset tumors. We was not mutated with without (MSS), although presented mutational patterns. Interestingly, only tumors. Furthermore, sporadic CRC (which usually caused hypermethylation) p53 but it hypermethylation genomic after analysing THBS1. addition, significantly located proximal colon. from (a hereditary form germline mismatch repair genes) never had mutations. We also analysed showing We frequency if hypermethylated, independently origin. And these codon 12, ones codons equally. carrying less than Finally, concluded differences suggest different modulation alternative activation pathways depending on background reliable, fast cheap tool for diagnosis exclude "