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 potential 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 to analyze the allelic deletions of Nm23 and p53 in colorectal carcinomas and to assess their prognostic significance in the evolution of the patients.


METHODS
Allelic deletions of Nm23 and p53 genes were studied in 56 colorectal carcinomas using different restriction fragment length polymorphisms. DNA ploidy and proliferative activity of the tumors were studied by flow cytometry. Actuarial disease free and overall survival were analyzed by the Kaplan--Meier method, and the curves were compared with the log rank test.


RESULTS
Thirty-eight patients were heterozygous 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 found in 63% of the 41 informative patients. All patients' tumors that had 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. No relationship was found between localization, invasion, lymph node metastasis, or proliferative index of the tumors and the allelic deletions of the Nm23-H1 or 17p13 locus. Nm23-H1 deletions were relatively more frequent in poorly differentiated adenocarcinomas (P = 0.03). A significant association between 17p13 deletions and DNA aneuploidy was found (P = 0.016). A similar tendency was observed with Nm23-H1 deletions (P = 0.051). Loss of Nm23-H1, but not of 17p13, was significantly associated with a shorter disease free (P = 0.025) and overall (P = 0.04) patient survival.


CONCLUSIONS
Allelic deletions of Nm23-H1 are significantly associated with a more aggressive behavior of colorectal carcinomas. 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 this locus is the specific target of the progression of these tumors.
Campo
E
E
Department of Anatomic Pathology, Hospital Clinico y Provincial, School of Medicine, University of Barcelona, Spain.
Miquel
R
R
Jares
P
P
Bosch
F
F
Juan
M
M
Leone
A
A
Vives
J
J
Cardesa
A
A
Yague
J
J
D000230:Adenocarcinoma / Q000235:genetics*; D000368:Aged; D000483:Alleles; D000782:Aneuploidy; D001483:Base Sequence; D015139:Blotting, Southern; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality; D005260:Female; D017353:Gene Deletion; D016158:Genes, p53; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins; D054778:NM23 Nucleoside Diphosphate Kinases; D009701:Nucleoside-Diphosphate Kinase; D016133:Polymerase Chain Reaction; D011379:Prognosis; D014157:Transcription Factors / Q000235:genetics*
D054778:NM23 Nucleoside Diphosphate Kinases; D014157:Transcription Factors; C517938:NME1 protein, human; D009701:Nucleoside-Diphosphate Kinase; D020559:Monomeric GTP-Binding Proteins