The role of p53 in tumor progression and prognosis in patients with primary colorectal cancer

Sammanfattning: Mutation in TP53 is the most common genetic alteration in human cancer. Alterations in p53 has mostly been related to poor prognosis in colorectal cancer, but this observation has not always been confirmed. The aim of the present study was to analyse the role of p53 in tumor progression and prognosis in colorectal cancer. TP53 was screened for mutations by Denaturing Gradient Gel Electrophoresis. Mutated samples were sequenced to confirm the exact nature of DNA alteration. IHC and ELISA were chosen for detection of stabilized p53 protein and presence of p53 antibodies in serum. I: Fourtyone liver resected patients were analysed for the presence of mutations in exons 5-9 of TP53 in both the primary tumors and corresponding liver metastases. All mutations found in primary tumors, were found in the corresponding liver metastases, while some patients had additional mutations in their liver metastases. Unexpectedly, liver resected patients with mutated TP53 had a statistically significant better prognosis than patients with wild type TP53. II: The presence of TP53 mutations were compared between two patient groups; one "potentially cured" and one with metastatic recurrence in the liver. Unexpectedly, potentially cured patients had a higher frequency of mutated p53. Potentially cured patients had significantly more mutations within the conserved region V, codon 273. All 10 mutations in potentially cured patients in the conserved region V, were Arg273His, whereas 3 of 4 were Arg273Cys in patients with metastatic recurrency.III: The predictive power of preoperative anti-p53 concentration in serum was compared to the presence of more traditional serum tumor markers as CEA, CA 50 and CA 242. P53 was a poor prognostic factor and did not add any power to the prediction by the classic tumor markers.IV: The presence of TP53 mutations in exons 7 and 8 were compared in cDNA and genomic DNA from the same tumor in 123 patients. The number of mutations differed between cDNA and genomic DNA, but there was no statisically significant difference in mutational spectra between cDNA and genomic DNA. The presence of total functional loss of p53 (defined as mutation + allelic loss) was also analysed. Only 5% of patients informative for LOH of p53 displayed a total functional loss of p53, which seems to be a much lower frequency than expected from the litterature.V: The aim was to analyse if any specific mutation i TP53 was related to anti-p53 production in patients with colorectal cancer. Sero-negative patients had more deletions than sero-positive patients, but without any statistically significant difference. The mutational spectra between sero-positive and sero-negative patients did not differ.P53 seem to be a poor and most likely a very complex prognostic factor in colorectal cancer. In conclusion, mutations in p53 may be important in malignant transformation, but less important for metastatic dissemination