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Whole-Genome Duplication and Genome Instability in Cancer Cells: Double the Trouble
Tsz Yin Lau1, Randy Y C Poon1,2
1Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
International Journal of Molecular Sciences
|February 25, 2023
Summary
Whole-genome duplication (WGD) in cancer cells creates genomic instability and facilitates evolution. Some cancer cells overcome WGD barriers, gaining a proliferative advantage and therapeutic resistance.
Area of Science:
- Genomics
- Cancer Biology
- Cell Biology
Background:
- Whole-genome duplication (WGD) is a frequent genomic alteration in cancer.
- WGD provides gene redundancy, buffering somatic mutations and promoting cancer evolution.
- WGD leads to increased DNA and centrosome burden, elevating genome instability.
Purpose of the Study:
- To chronicle the cellular events following whole-genome duplication in cancer.
- To elucidate the mechanisms by which cancer cells overcome WGD-associated barriers.
- To understand how WGD contributes to cancer cell proliferation and therapeutic resistance.
Main Methods:
- Review and synthesis of existing literature on WGD in cancer.
- Analysis of cell cycle events, including mitosis, DNA replication, and checkpoint regulation.
- Investigation of centrosome dynamics and spindle formation in polyploid cells.
Main Results:
- WGD is initiated by abortive mitosis (mitotic slippage, cytokinesis failure), leading to tetraploidization.
- Replication stress and DNA damage occur during the replication of the tetraploid genome.
- Supernumerary centrosomes cause chromosomal instability during subsequent mitoses.
Conclusions:
- Cancer cells employ mechanisms like p53-G1 checkpoint attenuation and pseudobipolar spindle formation to survive WGD.
- These adaptations result in genome instability, conferring a proliferative advantage to polyploid cancer cells.
- WGD-induced instability contributes to therapeutic resistance in a subset of polyploid cancers.
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