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Author Spotlight: Characterizing DNA Replication of Pathogenic Repeats to Uncover Mechanisms of Replication Fork Stalling and Expansion
Published on: September 13, 2024
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Recurrent repeat expansions in human cancer genomes.
Graham S Erwin1, Gamze Gürsoy2,3, Rashid Al-Abri4
1Department of Genetics, Stanford University, Stanford, CA, USA. gerwin@stanford.edu.
Nature
|December 14, 2022
Summary
Repeat expansions in DNA, known to cause diseases, are newly identified as a significant factor in various cancers. Researchers found specific repeat expansions linked to cancer subtypes and potential gene regulation, offering new avenues for cancer research.
Area of Science:
- Genomics
- Cancer Biology
- Molecular Genetics
Background:
- Tandem repeat (TR) expansions cause over 50 diseases, but their role in cancer is understudied.
- While microsatellite instability in short TRs is known in cancer, larger TR expansions remain largely uninvestigated.
- Existing research primarily focuses on neurological disorders, neglecting TR expansions in other diseases like cancer.
Purpose of the Study:
- To systematically identify and analyze tandem repeat expansions across diverse cancer types.
- To investigate the genomic distribution and potential regulatory roles of recurrent repeat expansions (rREs) in cancer.
- To explore the therapeutic potential of targeting specific repeat expansions in cancer cells.
Main Methods:
- Analysis of 2,622 cancer genomes from 29 distinct cancer types to identify TR expansions.
- Bioinformatic analysis to detect recurrent repeat expansions (rREs) and assess their genomic distribution.
- Long-read DNA sequencing for validation of specific rREs, including a GAAA-repeat expansion near UGT2B7.
- Preliminary in vitro experiments to assess the effect of targeting a specific rRE on cancer cell proliferation.
Main Results:
- Identified TR expansions in 2,622 cancer genomes across 29 cancer types.
- Discovered 160 recurrent repeat expansions (rREs) in seven cancer types, with most being subtype-specific.
- Found rREs are enriched near candidate cis-regulatory elements, suggesting a role in gene regulation.
- Detected a GAAA-repeat expansion near UGT2B7 in 34% of renal cell carcinoma samples, validated by sequencing.
- Observed a dose-dependent decrease in cancer cell proliferation upon treatment with a GAAA-targeting molecule in preliminary experiments.
Conclusions:
- Recurrent repeat expansions represent a significant and previously unexplored source of genetic variation in human cancer.
- The findings highlight the potential of rREs in driving cancer development and suggest their utility as cancer biomarkers.
- A comprehensive catalogue of rREs is provided, paving the way for further research into their functional roles and therapeutic targeting in oncology.
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