P53 TUMOR-SUPPRESSOR GENE STATUS AND THE DEGREE OF GENOMIC INSTABILITY IN SPORADIC COLORECTAL CANCERS

Background: Genomic instability reflects the propensity and the suscep tibility of the genome to acquire multiple alterations and, in turn, i s believed to be a driving force behind multistep carcinogenesis. Alth ough the molecular basis of genomic instability in sporadic colorectal cancers remains largely a mystery, mutation of the p53 tumor suppress or gene (also known as TP53) has been proposed to play an integral rol e in this process. However, a dilemma exists in that p53 mutation appe ars to be a late event in the progression of sporadic colorectal tumor s, whereas genomic instability, serving as a facilitator of tumor prog ression, is envisioned as occurring early in this process. Purpose: We evaluated the relationship between p53 mutation and the major form of genomic instability in sporadic colorectal tumors, namely, that invol ving DNA breakage, which leads to chromosomal translocations, insertio ns, deletions, and gene amplification. Methods: Fifty-eight sporadic c olorectal tumors that had been previously evaluated for genomic instab ility were analyzed for p53 mutations. These tumors were from consecut ively diagnosed patients. Genomic instability was quantified by use of inter-simple sequence repeat polymerase chain reaction analysis that employed (CA)(8)RG and (CA)(8)RY primers (R = purine [A or G]; Y pyrim idine [C or T]); a genomic instability index (a measure of the number of alterations in tumor DNA in comparison with normal DNA, expressed a s a percent) was calculated for each tumor. Mutation of the p53 gene i n exons 5-9 was determined by use of single-strand conformational poly morphism-polymerase chain reaction analysis and DNA sequencing. Chi-sq uared analysis was used to determine the statistical significance of d ifferences between groups of tumors. Reported P values are two-sided. Results: p53 mutations were identified in 29 (50%) of the 58 tumors. T he median genomic instability index value was 3.3%. Nineteen (65.5%) o f the 29 tumors with p53 mutations had genomic instability indices tha t were less than the median value (range, 0%-2.6%); the remaining 10 ( 34.5%) tumors had genomic instability indices that were greater than t he median (range, 3.9%-13.0%). Eleven (37.9%) of the 29 tumors with wi ld-type p53 genes had genomic instability indices that were less than the median value (range, 0%-2.6%), whereas the remaining 18 tumors had genomic instability indices above the median (range, 3.9%-11.7%). The re was a statistically significant association between a lesser degree of genomic instability and the presence of p53 mutations (P = .032). Conclusions and implications: Tumors with no or minimal evidence of ge nomic instability are more likely to harbor p53 mutations than tumors with evidence of substantial genomic instability. p53 mutations play a n important role in the development of cancers but do not appear to in itiate or promote genomic instability in sporadic colorectal tumors.