New Discoveries in the Development of Colon Cancer

Richard D. Kolodner
University of California at San Diego
R01ES11040

Background: Several forms of human colorectal cancer exist with the most frequent being the sporadic form. A variety of genetic mutations have been implicated in the development of this deadly disease. Sporadic defects in DNA mismatch repair genes play a role in either the initiation or progression of a number of tumor types. This observation suggests that other DNA repair genes could be involved in the development of colon cancer. One such gene known as Flap endonuclease 1 (Fen1) was investigated in this study. Fen1 is required for DNA replication and repair, and defects in the gene encoding Fen1 are known to cause accumulation of mutations and genomic rearrangements. Using gene knockout techniques, the investigators introduced a mutation into Fen1.

Advance: Genetic analysis of the mice used in this study showed that none were homozygous for the Fen1 mutation. This suggests that absence of Fen1 expression leads to embryonic lethality. Most of the mice heterozygous for the Fen1 mutation appeared normal, but further studies showed that when confined with a mutation in the adenomatous polyposis coli gene, double heterozygous animals have increased numbers of adenocarcinomas and decreased survival.

Implication: This study suggests that insufficiency of Fen1 expression may not make a difference to a cell undergoing normal replication, but if the cell cycle is perturbed by mutations in oncogenes or tumor suppressor genes, additional levels of a least some gene products might be necessary to accommodate the change in rates of cell division. If one or more products necessary for replication and repair is not present in the right quantities, the result may be detrimental to genomic stability. These results imply that a quantitative measure of the expression of some of these gene products may be useful as prognostic indicators of disease.

Citation: Kucherlapati M, Yang K, Kuraguchi M, Zhao J, Lia M, Heyer J, Kane MF, Fan K, Russell R, Brown AMC, Kneitz B, Edelmann W, Kolodner RD, Lipkin M, and Kucherlapati R. Haploinsufficiency of Flap endonuclease (Fen1) leads to rapid tumor progression. PNAS, July 23, 2002; 99; 15:9924-9929.