Study identifies DNA collisions driving genetic changes in cancer

DNA acts as a master copy of genetic information and must therefore remain consistent and error-free as cells divide and multiply across generations. The reliability of the DNA replication process depends on genome stability, which is maintained by DNA repair mechanisms that correct any mistakes that occur during DNA replication. Failures in these repair systems can introduce mutations and, ultimately, create genomic instability, which is strongly linked to cancer development. However, the underlying causes of such failures are not yet fully understood.

DNA consists of two strands in a double-helix structure. Each strand serves two primary purposes: acting as a template during DNA replication and providing instructions for protein synthesis in a process called transcription. Replication and transcription machinery can operate simultaneously on the same DNA molecule but usually remain at a safe distance. Occasionally, however, these two processes collide, causing what is known as a transcription and replication collision (TRC), which disrupts both processes and creates cellular stress. The role of TRCs in generating genomic instability in human cancers remains largely unexplored.

Through whole genome sequencing and analysis of thousands of tumor samples, the researchers detected multiple structural variations, including nucleotide deletions, duplications and translocations (where one part of the DNA is relocated to another).

For example, lung cancer is frequently driven by tobacco smoking, while melanoma is caused by UV exposure. The mutations resulting from tobacco carcinogens or UV light are distinct, as many different factors and cellular mechanisms contribute to mutation development.

"When thousands of mutations exist, identifying the specific signature representing an underlying mechanism or contributing factor for a particular subset of mutations is possible using mathematical decomposition, a math technique that breaks down complex genomic data into simple forms," Yang said.

The researchers analyzed data from 6,193 whole-genome-sequenced tumors to study TRCs' contributions to genomic instability. Structural variations in tumors resulting from collisions exhibit a unique signature, which can be detected through dosage imbalance -; a change in the number of copies at the DNA junctions, where strands of DNA join. This phenomenon occurs when extra copies of a DNA strand are mistakenly patched onto other DNA regions, causing structural variations. In some cases, this patching occurs near the original sequence, creating repetitive patterns known as tandem duplications (TDs).

One of the study's most promising findings was that cancers with large TDs are more sensitive to specific drugs, such as WEE1, CHK1 and ATR inhibitors. These drugs offer a potential treatment pathway for cancers characterized by high levels of TDs.

This study highlights innovative strategies for targeting tumors with specific gene mutations, offering hope for improved outcomes for patients with aggressive, hard-to-treat cancers.

The study, "Transcription and DNA replication collisions lead to large tandem duplications and expose targetable therapeutic vulnerabilities in cancer," was supported by the National Institutes of Health, University of Chicago, University of Chicago Medicine Comprehensive Cancer Center, Prostate Cancer Foundation, Department of Defense, Benioff Initiative for Prostate Cancer Research at UCSF and the Martha and Bruce Atwater Breast Cancer Research Program at UCSF.

Additional authors include Yang Yang, Xiaoming Zhong from the University of Chicago, Jonathan Chou, Michelle Badura, Patrick O'Leary, Henry Delavan, Troy Robinson, Emily Egusa, Jason Swinderman, Haolong Li, Meng Zhang, Minkyu Kim, Alan Ashworth and Felix Feng from University of California, San Francisco.

Source:

University of Chicago Medical Center

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