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Mathematical modeling the order of driver gene mutations in colorectal cancer

Lingling Li1,2, Yulu Hu2, Yunshan Xu3

  • 1School of Mathematics and Statistics, Shaanxi Normal University, Xi'an, China.

Plos Computational Biology
|June 27, 2023
PubMed

Insights

Understanding the gene mutation order in colorectal cancer (CRC) is key for personalized treatment. This study identified specific KRAS, APC, and TP53 mutation sequences that accurately predict CRC development across different ages.

Area of Science:

  • Oncology
  • Genetics
  • Mathematical Biology

Background:

  • Tumor heterogeneity presents significant challenges in cancer research and treatment.
  • Gene mutations and regulatory pathways drive tumor progression, necessitating personalized treatment approaches.
  • KRAS, APC, and TP53 are identified as critical driver genes in colorectal cancer (CRC).

Purpose of the Study:

  • To investigate the precise order of mutations in KRAS, APC, and TP53 genes during colorectal cancer development.
  • To identify mutation pathways that explain age-specific CRC incidence rates.
  • To provide a basis for understanding CRC pathogenesis and developing personalized therapies.

Main Methods:

  • Mathematical modeling was employed to analyze all possible mutation orders of KRAS, APC, and TP53.
  • The model was fitted using age-specific incidence data for colorectal cancer from the US Surveillance Epidemiology and End Results (SEER) registry (1973-2013).
  • Statistical analysis identified mutation orders that best explained the observed cancer incidence rates.

Main Results:

  • Specific mutation orders, including KRAS → APC → TP53, APC → TP53 → KRAS, and APC → KRAS → TP53, accurately explain age-specific CRC risk.
  • Eleven distinct gene mutation pathways were identified as plausible contributors to CRC development.
  • The APC gene alteration frequently acts as an initial or promoting event in colorectal cancer.

Conclusions:

  • The order of KRAS, APC, and TP53 gene mutations significantly influences colorectal cancer development and incidence.
  • The APC gene's role as an early event is highlighted across multiple identified mutation pathways.
  • Estimated mutation rates suggest the presence of genetic instability in colorectal cancer involving these key genes.

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