AIM:To determine correlations between family history,clinical features and mutational status of genes involved in the progression of colorectal cancer(CRC).METHODS:Histo-pathological features and molecular changes[KRAS,BRAF and CTNNB1 genes mutations,microsatellite instability(MSI)phenotype,expression of mismatch repair(MMR)and mucin(MUC)5AC proteins,mutation and expression analysis of TP53,MLH1promoter hypermethylation analysis]were examined in a series of 51 unselected Tunisian CRC patients,10 of them had a proven or probable hereditary disease,on the track of new tumoral markers for CRC susceptibility in Tunisian patients.RESULTS:As expected,MSI and MMR expression loss were associated to the presence of familial CRC(75%vs 9%,P<0.001).However,no significant associations have been detected between personal or familial cancer history and KRAS(codons 12 and 13)or TP53(exons 4-9)alterations.A significant inverse relationship has been observed between the presence of MSI and TP53 accumulation(10.0%vs 48.8%,P=0.0335)in CRC tumors,suggesting different molecular pathways to CRC that in turn may reflect different environmental exposures.Interestingly,MUC5AC expression was significantly associated to the presence of MSI(46.7%vs 8.3%,P=0.0039),MMR expression loss(46.7%vs8.3%,P=0.0039)and the presence of familial CRC(63%vs 23%,P=0.039).CONCLUSION:These findings suggest that MUC5AC expression analysis may be useful in the screening of Tunisian patients with high risk of CRC.