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Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
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Pervasive lesion segregation shapes cancer genome evolution
Sarah J Aitken1,2,3, Craig J Anderson4, Frances Connor1
1Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
Nature
|June 26, 2020
Summary
Most DNA lesions persist across cell divisions, leading to chromosome-scale mutation patterns. This explains how mutations generate genetic diversity and impacts cancer genome evolution.
Area of Science:
- Genetics
- Cancer Biology
- Genomics
Background:
- Cancer develops from genetic mutations and clonal expansion.
- The fate of DNA lesions and their impact on mutation patterns over cell cycles are not fully understood.
Purpose of the Study:
- To investigate the fate of mutagenic DNA lesions across multiple cell cycles.
- To understand how unrepaired DNA lesions contribute to mutation patterns and genetic diversity in cancer.
Main Methods:
- Analysis of mutagen-induced mouse liver tumors.
- Characterization of DNA lesion segregation and subsequent mutations.
- Examination of DNA replication across persistent lesions.
Main Results:
- Most mutagenic DNA lesions are not repaired in a single cell cycle but segregate into daughter cells.
- This segregation leads to chromosome-scale phasing of mutations.
- Replication across persistent lesions generates multiallelic and combinatorial genetic diversity.
- Lesion phasing allows precise measurement of repair bias, selection, and sister-chromatid exchange.
Conclusions:
- DNA lesion segregation is a fundamental process influencing mutation patterns across multiple cell generations.
- This mechanism contributes significantly to the genetic diversity observed in cancer genomes.
- Lesion segregation is a common feature of various mutagens, including UV light and chemotherapy agents, with broad implications for cancer evolution.
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