ABSTRACT
OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
Subject(s)
Carrier Proteins/genetics , Colorectal Neoplasms/genetics , Genes, p53 , MutS Homolog 2 Protein/genetics , Nuclear Proteins/genetics , Adaptor Proteins, Signal Transducing , Adult , Colorectal Neoplasms/epidemiology , Female , Humans , Immunohistochemistry , Incidence , Male , MutL Protein Homolog 1 , Oligonucleotide Array Sequence Analysis , Saudi Arabia/epidemiologyABSTRACT
OBJECTIVE: The gene encoding the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) is transcriptionally silenced by promoter hypermethylation in several human cancers including diffuse large B-cell lymphoma (DLBCL). We explored the aberrant promoter methylation of MGMT in Saudi diffuse large B-cell lymphoma and to investigate MGMT hypermethylation has an effect on patient's overall survival. METHODS: In a retrospective cohort study, 100 cases of DLBCL were collected from the Department of Pathology at King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia. We used methylation specific polymerase chain reaction to analyze the MGMT promoter methylation status in 100 tumor DNA of Saudi DLBCL patients receiving multi drug regimens. Tissue microarray (TMA) of these cases was also constructed. The MGMT protein expression was analyzed immunohistochemically. Molecular data were correlated with clinical outcome. RESULTS: Seventy one percent (71%) of 100 DLBCL patients showed MGMT promoter hypermethylation in their lymphoma. The presence of MGMT methylation was associated with statistically significant increase in the overall survival (p=0.02). The MGMT promoter hypermethylation was independent and a strong prognostic factor. CONCLUSION: The MGMT promoter hypermethylation appears to be useful marker for predicting survival in patient with DLBCL treated with multi drug regimens including cyclophosphamide, at the same time the study shows that TMA technology is useful for immunohistochemical analysis of large lymphoma populations.
