Stanford Advisors

Contact

  • Academic
    rschenck@stanford.edu
    University - Scholar Department: Stanford Cancer Institute Core Position: Postdoctoral Scholar

Additional Info

  • Mail Code: 5458
  • Profile:
    Computational biology postdoctoral scholar working to understand early cancer evolution and progression

All Publications

  • Homeostasis limits keratinocyte evolution PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Schencka, R. O., Kim, E., Bravo, R. R., West, J., Leedham, S., Shibata, D., Anderson, A. A. 2022; 119 (35): e2006487119

    Abstract

    Recent studies have revealed that normal human tissues accumulate many somatic mutations. In particular, human skin is riddled with mutations, with multiple subclones of variable sizes. Driver mutations are frequent and tend to have larger subclone sizes, suggesting selection. To begin to understand the histories encoded by these complex somatic mutations, we incorporated genomes into a simple agent-based skin-cell model whose prime directive is homeostasis. In this model, stem-cell survival is random and dependent on proximity to the basement membrane. This simple homeostatic skin model recapitulates the observed log-linear distributions of somatic mutations, where most mutations are found in increasingly smaller subclones that are typically lost with time. Hence, neutral mutations are "passengers" whose fates depend on the random survival of their stem cells, where a rarer larger subclone reflects the survival and spread of mutations acquired earlier in life. The model can also maintain homeostasis and accumulate more frequent and larger driver subclones if these mutations (NOTCH1 and TP53) confer relatively higher persistence in normal skin or during tissue damage (sunlight). Therefore, a relatively simple model of epithelial turnover indicates how observed passenger and driver somatic mutations could accumulate without violating the prime directive of homeostasis in normal human tissues.

    View details for DOI 10.1073/pnas.2006487119

    View details for Web of Science ID 000883462700001

    View details for PubMedID 35998218

    View details for PubMedCentralID PMC9436311