Mathematical modeling for mutator phenotype and clonal selection advantage in the risk analysis of lung cancer.

Abstract

Cancer is one of the leading diseases for human mortality. Although substantial research works have been conducted to investigate the initiation and progression of cancer disease, it is still an active debate regarding the function of mutations conferring a clone advantage and the importance of mutator phenotypes caused by the mutation of stability genes. To address this issue further, we develop a mathematical model based on the incidence data of non-small cell lung cancer and small cell lung cancer from the Surveillance Epidemiology and End Results registry in the USA. The key biological parameters have been analyzed to investigate the potential effective measures for inhibiting the risk of lung cancer. Although the first event is the gene mutation that leads to clonal expansion of cells for lung cancer, the simulation results show that the clonal advantage of cancer cells alone is insufficient to cause tumorigenesis. Our analysis suggests that mutations in genes that keep genetic stability are critical in the development of lung cancer. This implies that mutator phenotype is an important indicator for the diagnosis of lung cancer, which can enable early detection and treatment to reduce the risk of lung cancer effectively. Furthermore, the parameter analysis indicates that it would be highly effective to control the risk of lung cancer by inhibiting the transformation rate from the normal cells to mutated cells and the clonal expansion of cells with fewer gene mutations.