Abstract
Over 80% of human cancers originate from the epithelium, which covers the outer and inner surfaces of organs and blood vessels. In stratified epithelium, the bottom layers are occupied by stem and stem-like cells that continually divide and replenish the upper layers. In this work, we study the spread of premalignant mutant clones and cancer initiation in stratified epithelium, using the biased voter model on stacked two-dimensional lattices. Our main result is an estimate of the propagation speed of a premalignant mutant clone, which is asymptotically precise in the cancer-relevant weak-selection limit. We use our main result to study cancer initiation under a two-step mutational model of cancer, which includes computing the distributions of the time of cancer initiation and the size of the premalignant clone giving rise to cancer. Our work quantifies the effect of epithelial tissue thickness on the process of carcinogenesis, thereby contributing to an emerging understanding of the spatial evolutionary dynamics of cancer.
Funding Statement
EBG and KL were supported in part by NSF Grant CMMI-1552764. EBG, JF and KS were supported in part by NSF Grants DMS-1349724 and DMS-2052465. KL and JF were supported in part by the U.S.–Norway Fulbright Foundation and the Research Council of Norway R&D Grant 309273. EBG was supported in part by the Norwegian Centennial Chair grant.
Acknowledgments
The authors would like to thank the anonymous reviewer for a careful reading of the manuscript and for insightful comments and suggestions, which helped substantially improve the quality of the manuscript. We also thank the associate editor and the editor for their constructive comments.
Citation
Jasmine Foo. Einar Bjarki Gunnarsson. Kevin Leder. Kathleen Storey. "Spread of premalignant mutant clones and cancer initiation in multilayered tissue." Ann. Appl. Probab. 33 (1) 299 - 343, February 2023. https://doi.org/10.1214/22-AAP1816
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