Mathematical modeling the order of driver gene mutations in colorectal cancer.

Tumor heterogeneity is a large obstacle for cancer study and treatment. Different cancer patients may involve different combinations of gene mutations or the distinct regulatory pathways for inducing the progression of tumor. Investigating the pathways of gene mutations which can cause the formation of tumor can provide a basis for the personalized treatment of cancer. Studies suggested that KRAS, APC and TP53 are the most significant driver genes for colorectal cancer. However, it is still an open issue regarding the detailed mutation order of these genes in the development of colorectal cancer. For this purpose, we analyze the mathematical model considering all orders of mutations in oncogene, KRAS and tumor suppressor genes, APC and TP53, and fit it on data describing the incidence rates of colorectal cancer at different age from the Surveillance Epidemiology and End Results registry in the United States for the year 1973–2013. The specific orders that can induce the development of colorectal cancer are identified by the model fitting. The fitting results indicate that the mutation order with KRAS → APC → TP53, APC → TP53 → KRAS and APC → KRAS → TP53 explain the age–specific risk of colorectal cancer with very well. Furthermore, eleven pathways of gene mutations can be accepted for the mutation order of genes with KRAS → APC → TP53, APC → TP53 → KRAS and APC → KRAS → TP53, and the alternation of APC acts as the initiating or promoting event in the colorectal cancer. The estimated mutation rates of cells in the different pathways demonstrate that genetic instability must exist in colorectal cancer with alterations of genes, KRAS, APC and TP53. Author summary: Cumulative mutations in driver genes are the essential cause of cancer disease. For the colorectal cancer, KRAS, APC and TP53 are the common driver genes, and approximately 15% patients with colorectal cancer carry all mutations of the three genes. Exploring the pathway of mutations in these gene is extremely useful for the diagnosis and treatment of cancer. However, the mutation orders of these genes may vary in different patients due to the heterogeneity of tumor. Hence, we discuss all possible mutation orders in the genes, KRAS, APC and TP53 by using the model with five hits and find out the mutation pathways of genes that can effectively fit the incidence rate of colorectal cancer at different age in this article. In addition, we give the estimated values of mutation rates in each pathway that can explain the procession of colorectal cancer. The results obtained can offer guidelines to the treatment strategy of colorectal cancer. [ABSTRACT FROM AUTHOR]