Wv. Kastrinakis et al., INCREASED INCIDENCE OF P53 MUTATIONS IS ASSOCIATED WITH HEPATIC METASTASIS IN COLORECTAL NEOPLASTIC PROGRESSION, Oncogene, 11(4), 1995, pp. 647-652
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.