PROGNOSTIC-SIGNIFICANCE OF THE LOSS OF HETEROZYGOSITY OF NM23-H1 AND P53 GENES IN HUMAN COLORECTAL CARCINOMAS

Background. Nm23 is a gene associated with low tumor metastatic potent ial and has been proposed to be a metastasis suppressor gene. Nm23 is localized on chromosome 17q21.3-22, whereas the p53 suppressor gene is on 17p13. Allelic deletions of chromosome 17 have been related to the progression of colorectal carcinomas. The purpose of this study was t o analyze the allelic deletions of Nm23 and p53 in colorectal carcinom as and to assess their prognostic significance in the evolution of the patients. Methods. Allelic deletions of Nm23 and p53 genes were studi ed in 56 colorectal carcinomas using different restriction fragment le ngth polymorphisms. DNA ploidy and proliferative activity of the tumor s were studied by flow cytometry. Actuarial disease free and overall s urvival were analyzed by the Kaplan-Meier method, and the curves were compared with the log rank test. Results. Thirty-eight patients were h eterozygous for Nm23 gene (68%), and 9 of them (24%) exhibited a loss of heterozygosity in the tumor sample. One of the homozygous patients showed a loss of both Nm23 alleles. Allelic deletions of 17p13 were fo und in 63% of the 41 informative patients. All patients' tumors that h ad loss of heterozygosity of the Nm23-H1 locus also had allelic losses on the short arm of chromosome 17 (17p13) and in other loci on 17q. N o relationship was found between localization, invasion, lymph node me tastasis, or proliferative index of the tumors and the allelic deletio ns of the Nm23-H1 or 17p13 locus. Nm23-H1 deletions were relatively mo re frequent in poorly differentiated adenocarcinomas (P = 0.03). A sig nificant association between 17p13 deletions and DNA aneuploidy was fo und (P = 0.016). A similar tendency was observed with Nm23-H1 deletion s (P = 0.051). Loss of Nm23-H1, but not of 17p13, was significantly as sociated with a shorter disease free (P = 0.025) and overall (P = 0.04 ) patient survival. Conclusions. Allelic deletions of Nm23-H1 are sign ificantly associated with a more aggressive behavior of colorectal car cinomas. The loss of this gene seems to be part of extensive deletions of chromosome 17, and it is also associated with DNA aneuploidy. More studies are needed to determine whether Nm23-H1 or a gene linked to t his locus is the specific target of the progression of these tumors.