School of Mathematics and Statistics, Shaanxi Normal University, Xi'an, China.
School of Science, Xi'an Polytechnic University, Xi'an, China.
PLoS Comput Biol. 2023 Jun 27;19(6):e1011225. doi: 10.1371/journal.pcbi.1011225. eCollection 2023 Jun.
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 orders 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.
肿瘤异质性是癌症研究和治疗的一大障碍。不同的癌症患者可能涉及不同基因突变的组合或不同的诱导肿瘤进展的调节途径。研究导致肿瘤形成的基因突变途径可为癌症的个体化治疗提供依据。研究表明，KRAS、APC 和 TP53 是结直肠癌最重要的驱动基因。然而，这些基因在结直肠癌发展过程中的详细突变顺序仍然是一个悬而未决的问题。为此，我们分析了考虑癌基因、KRAS 和抑癌基因 APC 和 TP53 中所有突变顺序的数学模型，并将其拟合在美国 1973-2013 年监测流行病学和最终结果登记处描述的不同年龄结直肠癌发病率数据上。通过模型拟合确定了可诱导结直肠癌发展的特定顺序。拟合结果表明，KRAS→APC→TP53、APC→TP53→KRAS 和 APC→KRAS→TP53 的突变顺序可以很好地解释结直肠癌的特定年龄风险。此外，对于 KRAS→APC→TP53、APC→TP53→KRAS 和 APC→KRAS→TP53 的基因突变顺序，可以接受十一条基因突变途径，并且 APC 的交替作为结直肠癌中的起始或促进事件。不同途径中细胞的估计突变率表明，KRAS、APC 和 TP53 基因改变的结直肠癌中必须存在遗传不稳定性。
