Mathematical modeling the order of driver gene mutations in colorectal cancer

Abstract

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.

High-Throughput Mass Spectrometry Analysis of N-Glycans and Protein Markers after FUT8 Knockdown in the Syngeneic SW480/SW620 Colorectal Cancer Cell Model

“…Massive parallel sequencing methodologies can thus be used to detect myriad (epi)­genetic and susceptibility loci alterations that, gradually accumulating over 10 to 15 years, give rise to colorectal mucosa cancerization and the subsequent invasiveness and spread of CRC . However, the mutational sequences of CRC-determining genes, such as KRAS , APC , or TP53 , are still under discussion . For their part, high-throughput proteomic platforms hold the promise of revealing the proteins that drive the malignant evolution of colorectal cells.…”

“… 4 However, the mutational sequences of CRC-determining genes, such as KRAS , APC , or TP53 , are still under discussion. 5 For their part, high-throughput proteomic platforms hold the promise of revealing the proteins that drive the malignant evolution of colorectal cells. In this regard, mass spectrometry (MS)-based proteomics facilitates comprehensive and systematic protein signatures for the accelerated profiling of putative diagnostic and prognostic biomarkers.…”

Order-of-Mutation Effects on Cancer Progression: Models for Myeloproliferative Neoplasm

“…While a multi-hit model has recently been extended to enumerate mutations according to order of appearance in colorectal cancer (KRAS, APC and TP53) (Li et al. 2023 ) and to compute probabilities of specific mutation trajectories, it does not address gene interactions or the mechanisms behind order-of-mutation effects. However, recent data derived from patients with myeloproliferative neoplasm (MPN), a cancer of the bone marrow (Ortmann et al.…”

“…Moreover, our nonlinear physical models are sufficiently simple and general enough that they can be used to model other cancers (Li et al. 2023 ) and other processes such as cellular adaptation (Brooks et al. 2011 ).…”