Role of Heterozygous APC Mutation in Niche Succession and Initiation of Colorectal Cancer – A Computational Study

Mutations in the adenomatous polyposis coli (APC) gene are found in most colorectal cancers. They cause constitutive activation of proliferative pathways when both alleles of the gene are mutated. However studies on individuals with familial adenomatous polyposis (FAP) have shown that a single mutated APC allele can also create changes in the precancerous colon crypt, like increased number of stem cells, increased crypt fission, greater variability of DNA methylation patterns, and higher somatic mutation rates. In this paper, using a computational model of colon crypt dynamics, we evolve and investigate a hypothesis on the effect of heterozygous APC mutation that explains these different observations. Based on previous reports and the results from the computational model we propose the hypothesis that heterozygous APC mutation has the effect of increasing the chances for a stem cell to divide symmetrically, producing two stem cell daughters. We incorporate this hypothesis into the model and perform simulation experiments to investigate the consequences of the hypothesis. Simulations show that this hypothesis links together the changes in FAP crypts observed in previous studies. The simulations also show that an APC+/− stem cell gets selective advantages for dominating the crypt and progressing to cancer. This explains why most colon cancers are initiated by APC mutation. The results could have implications for preventing or retarding the onset of colon cancer in people with inherited or acquired mutation of one APC allele. Experimental validation of the hypothesis as well as investigation into the molecular mechanisms of this effect may therefore be worth undertaking

Flavin-containing monooxygenase 3 gene polymorphisms in Turkish population

Flavin-containing monooxygenases (FMOs) represent the second most important human monooxygenase system, after cytochrome P450s (CYPs) and catalyze the oxygenation of many chemicals containing nitrogen-, sulphur-, phosphorous-, selenium-and other nucleophilic heteroatoms. FMO3 is the prominent FMO form in adult human liver. For FMO3, both interindividual variability within a single ethnic group and variability between ethnic groups have been reported. In our study, three prevalent functional FMO3 variants (E158K, V257M, and E308G) were genotyped in healthy Turkish people by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) methods. The frequencies of alleles and haplotypes were compared with those obtained from different populations. It was found that FMO3 158K, 257M and 308G alleles, demonstrate impaired metabolism toward many FMO3 substrates, were observed frequently in Turkish population similar to the other populations. Also, the frequencies of haplotypes were determined based on individual allelic frequencies and it was observed that the most common haplotypes were haplotip EVE and KVE (E158K/V257M/E308G), which together accounted for 80% of all haplotypes. The obtained data from the present study could be useful for further studies assessing sensitivity to therapeutic drugs, environmental toxicants and common disease