INCREASED INCIDENCE OF P53 MUTATIONS IS ASSOCIATED WITH HEPATIC METASTASIS IN COLORECTAL NEOPLASTIC PROGRESSION

Within a panel of 15 colon carcinoma cell lines we have characterized the p53 gene status using immunocytochemistry (ICC), SSCP and direct s equence analysis. Extension of this analysis to the use of ICC on 104 colonic lesions, representative of different stages of colonic neoplas tic progression, showed an absence of detectable p53 nuclear staining in preneoplastic polyp lesions (20 cases) with staining of 52% (25/48) of primary colon carcinomas and 81% (29/36) of hepatic metastases, su ggestive of an increased incidence of p53 mutations in late stage lesi ons of colonic cancer. To address this issue more directly, we analyse d 18 primary colon carcinomas and hepatic metastases excised coinciden tally from the same patients. In ICC, p53 nuclear staining was recorde d in matching lesions from eight individuals where direct sequencing r evealed identical mutations in each case. In four individuals no ICC s taining was detected in either lesion and molecular analysis revealed wild type sequence in exons 4-9. In six individuals p53 nuclear staini ng was observed in the hepatic metastases of patients but not the prim ary lesion. Molecular analysis revealed point mutation events in hepat ic metastases from these patients which were not detected in the prima ry tumor. The point mutations identified in colon carcinomas were pred ominantly transition events (83%) located in previously characterized codon hotspot regions. These results demonstrate an increased incidenc e of p53 mutations associated with secondary lesions of colorectal tum ors suggestive of a role for p53 in the establishment of colorectal he patic metastases.