Colorectal carcinomas from Middle East. Molecular and tissue microarray analysis of genomic instability pathways

To evaluate the overall incidence of microsatellite instability [MSI], hereditary non polyposis colorectal cancer, and tumor supressor gene [TP53] mutations in Saudi colorectal carcinomas. We studied the MSI pathway in Saudi colorectal cancers [CRC] from 179 unselected patients using 2 methods: MSI by polymerase chain reaction, and immunohistochemistry detection of mutL homologs 1 and mutS homologs 2 proteins. The TP53 mutations were studied by sequencing exons 5, 6, 7, and 8. Of the 150 colorectal carcinomas analyzed for MSI, 16% of the tumors showed high level instability [MSI-H], 19.3% had low-level instability [MSI-L] and the remaining 64% tumors were stable. Survival of the MSI-H group was better as compared to the MSI-L or microsatellite stable group [p=0.0217]. In the MSI-H group, 48% were familial MSI tumors, which could be attributable to the high incidence of consanguinity in the Saudi population. The TP53 mutations were found in 24% of the cases studied. A high proportion of familial MSI cases and a lower incidence of TP53 mutations are some of the hallmarks of the Saudi colorectal carcinomas, which need to be explored further

Colorectal carcinoma from Saudi Arabia Analysis of MLH-1, MSH-2 and p53 genes by immunohistochemistry and tissue microarray analysis

To document the incidence and role of p53 and DNA mismatch repair proteins in colorectal carcinomas, and to evaluate the relative frequency of major molecular pathways in colorectal cancers from Saudi Arabia. We collected the formalin fixed, paraffin embedded tissues from 154 colorectal tumors [83 patients from King Faisal Specialist Hospital and Research Centre and 71 from Saudi Aramco Dhahran Health Centre] between January 1989 and December 2003. We analyzed the p53 and mismatch repair gene expression [hMSH-2, hMLH-1] by immunohistochemistry in tissue microarray format. Expression loss of at least one mismatch repair gene was found in 33.8% of cases and significantly associated with the right-sided tumor location [p=0.0047]. The p53 positivity was observed in 57.5% of tumors, and was inversely linked to expression loss of mismatch repair genes [P=0.0102]. The strong confirmation of the previously established associations between tumor phenotype, and mismatch repair gene alteration provided strong evidence for the validity of our experimental approach. Together with the higher incidence of right sided location in Saudi [46.6%] than in Western colon cancers [34.9%], the observed high prevalence of mismatch gene expression loss in Saudi tumors argues for a higher importance of microsatellite instability in this population. If confirmed, it will be interesting to see whether an increased level of familial or sporadic microsatellite instability cases is causing this variation

Wingless signaling pathway family relation to colon cancer. Have we come full circle?

Colorectal cancer CRC is one of the most common malignancies worldwide. Advances in molecular techniques have provided deep insight into the molecular pathogenesis, biologic and genetic changes occurring in colon cancer patients. Current theories of malignant transformation postulate that development of colon cancer is related to 2 main pathways; the loss of heterozygosity pathway, which is usually due to a defect in the adenomatous polyposis coli APC gene and microsatellite instability, which is usually due to a defect in mismatch repair MMR genes. This review summarizes the role of the wingless signaling pathway genes including APC and MMR genes in the development of CRC