By Kimberly Mann Bruch —
A team of U.S. researchers has created a comprehensive map of how cancer rewires the cellular machinery that controls gene activity, potentially opening new avenues for targeted treatments.
The team’s findings reveal that tumors don’t just accumulate random genetic damage—they systematically reorganize the three-dimensional architecture of DNA to their advantage. The National Institutes of Health (NIH)-funded study was published in Nature Genetics and analyzed 69 tumor samples from 15 different types of human cancer, and led by researchers from multiple institutions – including the University of California San Diego.
“Our work is part of the Cancer Genome Atlas Analysis Network and our ultimate goal is to better understand how cancer systematically reorganizes gene control,” said UC San Diego Professor Vineet Bafna, a leader in bioinformatics research and faculty member in the Department of Computer Science and Engineering at the UC San Diego Jacobs School of Engineering. “Ultimately, our findings can help cancer researchers develop new therapeutic strategies.”
At UC San Diego, Bafna holds a Halıcıoğlu Data Science Institute Chancellor’s Endowed Chair. The Halıcıoğlu Data Science Institute (HDSI) is part of the UC San Diego School of Computing, Information and Data Sciences (SCIDS).
Cancer’s Strategic Gene Control
Bafna explained that even though every cell in the human body contains the same DNA, different genes are turned on or off depending on the cell type and situation. This process is controlled by regulatory elements called enhancers, which can influence genes located far away on the chromosome by physically interacting with them in three-dimensional space.
“Our multi-institution team’s study showed that cancer exploits this system in surprisingly organized ways,” said Kaiyuan Zhu, an HDSI postdoctoral scholar. “We identified three distinct patterns of how tumors manipulate enhancer activity across more than 100 cancer-driving genes (oncogenes).”
The increased expression of oncogenes can occur through their physically increased copy numbers, or up-regulation by distant enhancers through enhancer rewiring, where oncogenes become connected to regulatory elements that are normally located far away on the genome. This latter pattern is very complex because tumors completely restructure which enhancers control each gene.
Beyond the Tumor: Immune System Implications and Enhancer Rewiring
In addition to showing the three patterns of tumor manipulation, the study also mapped enhancer activity in non-cancerous cells within the tumor environment – revealing how tumors may influence surrounding immune cells to avoid detection and destruction.
“This finding could help explain why some cancers successfully evade the human body’s natural defenses,” Bafna said. “Using advanced DNA sequencing techniques, we discovered that different types of genetic alterations have distinct effects on enhancer rewiring.”
Specifically, the team found that point mutations (single DNA letter changes) in non-coding regions can disrupt normal enhancer function and that chromosomal inversions and translocations create new, abnormal connections between enhancers and genes. Additionally, the study showed that gene amplifications—particularly those occurring on extrachromosomal DNA fragments—cause the most extensive rewiring.
“The extrachromosomal DNA finding is particularly significant, as these free-floating genetic elements can multiply rapidly and dramatically alter gene regulation patterns,” Zhu said. “Rather than targeting individual mutated genes, future treatments might focus on disrupting the abnormal enhancer networks that tumors depend on.”
The systematic approach developed in this study provides a new framework for analyzing genome topology across different cancer types, potentially accelerating the development of precision therapies tailored to individual tumor’s specific regulatory rewiring patterns.
“Our work represents a major step forward in understanding cancer not just as a collection of genetic mutations, but as a disease that strategically reengineers the fundamental control systems of cellular life,” Vineet Bafna, Halıcıoğlu Data Science Institute Chancellor’s Endowed Chair
This research was supported in part by the U.S. National Institutes of Health (grant nos. U24CA264379, R01GM114362, U24CA264032 and R01CA218668).
