INDUCTION OF INCREASED SALVAGE PATHWAYS OF NUCLEOTIDE SYNTHESIS BY DOSAGE EFFECT DUE TO CHROMOSOME IMBALANCES MAY BE FUNDAMENTAL IN CARCINOGENESIS - THE EXAMPLE OF COLORECTAL-CARCINOMA

Abstract

The cytogenetic study of colorectal carcinomas is consistent with the following sequence in the tumor evolution: rearrangement of chromosome 17 with loss of 17p and often gain of 17q, loss of chromosome 18, frequent del(5q), frequent del(1p) correlated with the gain of an early replicating X. At least one gene directly involved in nucleotide synthesis, especially in the de novo pathways for thymidine is located on each of these chromosomes or chromosomes segments. A model established on the gene dosage effect, which likely results of these chromosome imbalances, may be proposed: (1) increase of thymidine kinase activity (chromosome 17q) and thus of the salvage pathway of thymidine synthesis (2) decrease of thymidine de novo pathways by decrease of thymidylate synthase (chromosome 18) and of dihydrofolate reductase (chromosome 5q) and thus accumulation of 2''-deoxyuridine-5''P, which saves 2''-deoxycytidine 5-P (3) decrease of cytidylate (or uridylate) kinase (chromosome 1p) and thus accumulation of 2-deoxycytidine-5-PP and of uridine-5-P (UMP) decreasing the metabolisation of orotidine-5''-P, precursor of 2-deoxycytidine-5-PP, which (4) saves -D-5-ribosyl-PP (PRPP) or even conversion of orotidine-5''-P in PRPP. The latter is the immediate precursor of nucleotides in their major salvage pathways synthesis: PRPP + base .fwdarw. nucleotide + PPi. This reaction which would be much activated needs hypoxanthine phosphorybosyl transferase (HPRT). Its gene is carried by chromosome X which is here duplicated in its active early replicating form. The gene for another enzyme necessary for PRPP synthesis (PRPP synthetase) is also carried by chromosome X. If this model is correct, it shows that the chromosomal changes, which are secondary events in tumor evolution, progressively develop a very sophisticated metabolic change favouring salvage pathways of nucleotide synthesis to the detriment of de novo pathways. The same principle can be applied to other tumors. It sheds a new light on the understanding of tumorigenesis and may lead to a better adaptation of chemotherapy, in relation with observed chromosome imbalances.