Fluctuating methylation clocks for cell lineage tracing at high temporal resolution in human tissues

Journal article

Cancer development is a multistep process often starting with a single cell in which a number of epigenetic and genetic alterations have accumulated thus transforming it into a tumor cell. The progeny of such a single benign tumor cell expands in the tissue and can at some point progress to malignant tumor cells until a detectable tumor is formed. The dynamics from the early phase of a single cell to a detectable tumor with billions of tumor cells are complex and still not fully resolved, not even for the well-known prototype of multistage carcinogenesis, the adenoma-adenocarcinoma sequence of colorectal cancer. Mathematical models of such carcinogenesis are frequently tested and calibrated based on reported age-specific incidence rates of cancer, but they usually require calibration of four or more parameters due to the wide range of processes these models aim to reflect. We present a cell-based model, which focuses on the competition between wild-type and tumor cells in colonic crypts, with which we are able reproduce epidemiological incidence rates of colon cancer. Additionally, the fraction of cancerous tumors with precancerous lesions predicted by the model agree with clinical estimates. The correspondence between model and reported data suggests that the fate of tumor development is majorly determined by the early phase of tumor growth and progression long before a tumor becomes detectable. Due to the focus on the early phase of tumor development, the model has only a single fit parameter, the time scale set by an effective replacement rate of stem cells in the crypt. We find this effective rate to be considerable smaller than the actual replacement rate, which implies that the time scale is limited by the processes succeeding clonal conversion of crypts.Comment: 28 pages, 13 figure

Authors: Gabbutt, C; Schenck, RO; Weisenberger, DJ; Kimberley, C; Berner, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Biotechnology
• Volume: 40
• Issue: 5
• Pages: 720-730
• Publication date: 2022-01-03
• DOI: 10.1038/s41587-021-01109-w
• EISSN: 1546-1696
• ISSN: 1087-0156
• Language: English
• Keywords: Crypt; Gene expression; Gene; Biology; DNA; Stem cell; CpG site; Genetics; Cell division; Cell biology; Cell; Methylation; Somatic cell; DNA methylation