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.
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 decreased 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 later is the immediate precursor of nucleotides in their major salvage pathways synthesis: PRPP + base----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.(ABSTRACT TRUNCATED AT 250 WORDS)
D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002900:Chromosomes, Human, 1-3; D002902:Chromosomes, Human, 16-18; D002905:Chromosomes, Human, 4-5; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D009711:Nucleotides / Q000096:biosynthesis* / Q000235:genetics; D010754:Phosphoribosyl Pyrophosphate / Q000096:biosynthesis; D012004:Rectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D012268:Ribose-Phosphate Pyrophosphokinase / Q000235:genetics; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D013936:Thymidine / Q000096:biosynthesis; D013937:Thymidine Kinase / Q000235:genetics; D013940:Thymidylate Synthase / Q000235:genetics; D014541:Uridine Kinase / Q000235:genetics; D014960:X Chromosome
D009711:Nucleotides; D010754:Phosphoribosyl Pyrophosphate; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D013937:Thymidine Kinase; D014541:Uridine Kinase; D012268:Ribose-Phosphate Pyrophosphokinase; D013936:Thymidine