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Quantifying cell divisions along evolutionary lineages in cancer
Martin Blohmer1,2,3, David M Cheek1,2, Wei-Ting Hung2,4
1Department of Genetics, Harvard Medical School, Boston, MA, USA.
Nature Genetics
|February 5, 2025
Summary
We developed a simple method to count cell divisions using DNA replication mutations. This reveals cancer evolution, showing more divisions correlate with metastasis and poorer survival in colorectal and lung cancers.
Area of Science:
- Cancer Biology
- Genetics
- Evolutionary Biology
Background:
- Cell division is fundamental to somatic evolution and cancer progression.
- Quantifying cell divisions in human cancers has been a significant challenge.
- Understanding cell division history is crucial for cancer research.
Purpose of the Study:
- To develop and validate a novel framework for quantifying cell divisions in cancer.
- To investigate the relationship between cell division history and cancer evolution milestones.
- To explore the link between cell division burden, metastatic capacity, and patient survival.
Main Methods:
- Developed a framework to count cell divisions by analyzing DNA replication-related mutations in polyguanine homopolymers.
- Applied the framework to analyze 505 samples from 37 colorectal cancer patients.
- Analyzed a cohort of 73 multifocal lung cancer samples.
Main Results:
- Colorectal cancer primary tumors diversify at approximately 250 cell divisions, while distant metastases diverge at around 500 divisions.
- Distant metastases, unlike lymph node metastases, originate from primary tumor regions with surplus divisions, linking proliferation to metastatic potential.
- In lung cancer, the cell division burden of the common ancestor distinguishes independent primary tumors from metastases and correlates with patient survival.
Conclusions:
- The developed framework provides an accessible method to determine cancer cell division history.
- Cell division history contains valuable biological and clinical information, particularly regarding metastatic capacity and patient prognosis.
- Extensive proliferation is a key factor associated with metastatic potential in both colorectal and lung cancers.
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