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• W191304586 abstract "La via Ras-Raf-MAPK regula funcions cellulars com la proliferacio, la transformacio o lapoptosi. En cancer sol presentar mutacions activants en algun dels tres gens que codifiquen per a Ras (KRAS, HRAS y NRAS) i en un dels gens que codifiquen per a Raf (BRAF). A mes, les mutacions de Ras i Raf son events alternatius ja que mai es donen a la vegada en un mateix tumor, suggerint que aquestes mutacions activen a la mateixa via. En cancer colorectal (CCR) la mutacio puntual de BRAF V600E sassocia significativament als casos que presenten inestabilitat de microsatellits (MSI) que solen presentar mutacions per insercio o delecio a sequencies repetitives.En aquesta tesi hem volgut determinar possibles associacions moleculars o clinico-patologiques de la mutacio V600E que permetin explicar lalta capacitat tumorogenica daquesta mutacio en aquest tipus especific de tumor. Aixi, en cancer gastric, que en MSI presenta un patro mutacional molt semblant al colorectal, no hem detectat mutacions de BRAF, ni en casos estables (MSS) ni en MSI, mentre que si que hem confirmat lassociacio daquesta mutacio a MSI en CCR. Sorprenentment, les mutacions de KRAS en cancer gastric tambe sassocien significativament a MSI, mentre que en CCR es troben a ambdos fenotips (MSS i MSI).Per un altre costat, en CCR MSI esporadic, que sol estar provocat per lhipermetilacio del gen MLH1, no hem trobat cap associacio de BRAF-V600E amb mutacions als gens KRAS, APC ni p53. En canvi, si que hem detectat una clara associacio de V600E amb lhipermetilacio de MLH1. A mes, analitzant els mateixos tumors per la metilacio dels gens p16, p14, RASSF1A, APC, MGMT i THBS1 hem associat BRAF-V600E i lhipermetilacio de MLH1 a un estat dhipermetilacio genomica. Duna altra banda, no hem trobat cap associacio de BRAF amb cap caracteristica clinico-patologica a excepcio de la localitzacio ja que BRAF-V600E es detecta significativament en els casos proximals. Tambe hem analitzat casos de CCR de pacients HNPCC, que tenen MSI per mutacions germinals enlloc de per metilacio. No hem detectat cap mutacio V600E de BRAF en aquests tumors, tant si tenen mutacions germinals a MLH1, MSH2 o MSH6 o no tenen mutacio coneguda pero compleixen criteris clinics com els dAmsterdam o els de Bethesda mes estrictes. Aixo confirma que V600E no es dona especificament als casos MSI sino en els casos amb hipermetilacio de MLH1, i que aquests solen tenir mes metilacio genomica que la resta de tumors.Apart, tambe hem analitzat KRAS en casos de CCR MSS, MSI esporadics amb i sense hipermetilacio de MLH1 i HNPCC. Aixi, la frequencia de mutacions a KRAS es mes alta si no hi ha hipermetilacio de MLH1, independentment del seu origen esporadic o hereditari. No obstant, en els casos esporadics aquestes mutacions afecten sobretot al codo 12 mentre que en els casos hereditaris afecten al codo 12 i al 13 equitativament. A mes, els casos HNPCC amb mutacio a MLH1 tenen una frequencia de mutacions a KRAS menor que si la mutacio germinal te lloc a MSH2 o MSH6. Finalment, les diferencies mutacionals de KRAS i BRAF en CCR esporadic i hereditari suggereixen una modulacio diferent de la via Ras-Raf-MAPK aixi com una possible activacio daltres vies moleculars alternatives depenent de lestat en que es trobi el fons genetic i epigenetic del tumor. A mes, labsencia total de la mutacio V600E de BRAF a HNPCC la converteix en una eina fiable, rapida i de baix cost per al diagnostic molecular com a criteri dexclusio de cancer familiar. SUMMARY:The Ras-Raf-MAPK pathway regulates functions such as cell proliferation, transformation and apoptosis. In cancer activating mutations are present in the three Ras genes (KRAS, HRAS and NRAS) and in one Raf gene (BRAF). Moreover, Ras and Raf mutations hardly ever are found together in the same tumor suggesting that they activate the same pathway. In colorectal cancer (CRC) the BRAF hotspot mutation V600E is associated to microsatellite instability (MSI), which is characterised by insertion/deletion mutations in repetitive sequences. Here we have determined possible molecular or clinico-pathological associations of V600E to understand its higher tumorogenic capabilities in this subset of tumors.We found that BRAF was not mutated in gastric cancer with MSI or without (MSS), although gastric and colorectal MSI tumors presented the same mutational patterns. Interestingly, gastric cancer only presented KRAS mutations in MSI tumors. Furthermore, in sporadic MSI CRC (which is usually caused by MLH1 hypermethylation) BRAF-V600E was not associated to KRAS, APC or p53 mutations but it was to MLH1 hypermethylation and to genomic hypermethylation after analysing p16, p14, RASSF1A, APC, MGMT and THBS1. In addition, V600E was associated significantly to tumors located in the proximal colon. Moreover, tumors from HNPCC (a hereditary form of MSI cancer caused by germline mutations in mismatch repair genes) never had V600E mutations.We have also analysed KRAS in CRC showing MSS, sporadic MSI with or without MLH1 hypermethylation and HNPCC. We found that KRAS mutation frequency is higher if MLH1 is not hypermethylated, independently of its sporadic or hereditary origin. And although in sporadic tumors these mutations are located in codon 12, in the hereditary ones they are located in codons 12 or 13 equally. Furthermore, HNPCC tumors carrying germline MLH1 mutations have less KRAS mutations than tumors with germline mutations in MSH2 or MSH6. Finally, we concluded that KRAS and BRAF differences in sporadic and hereditary CRC suggest a different Ras-Raf-MAPK modulation and possible alternative activation pathways depending on the genetic and epigenetic background of the tumor. Moreover, V600E is a reliable, fast and cheap tool for HNPCC diagnosis to exclude a hereditary origin. " @default.
• W191304586 created "2016-06-24" @default.
• W191304586 creator A5070543696 @default.
• W191304586 date "2007-02-27" @default.
• W191304586 modified "2023-09-26" @default.
• W191304586 title "Alteracions de la VIA RAS-RAF en càncer gastrointestinal amb defectes de reparació genòmica" @default.
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