Unexpected chromosome interaction fuels aggressive cancers, researchers discover
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Published in Nature, researchers at the University of Pittsburgh School of Medicine and UPMC Hillman Cancer Center report a previously unrecognized change in how the cell's genetic material is packaged into structures called chromosomes that helps explain how some aggressive cancers sustain unlimited growth.
In a subset of tumors known as ALT-positive (ALT+) cancers, the team found that DNA normally associated with centromeres—the central regions of chromosomes—can be inserted near telomeres, the chromosome ends. Because this pattern appears in patient tumors, including pediatric brain cancers, it could serve as a biomarker to identify tumors driven by these unusual genetic rearrangements and track their evolution over time.
"This is something that nobody expected. These are two parts of the chromosome that are never supposed to interact," said senior author Roderick O'Sullivan, Ph.D., professor in the Department of Pharmacology and Chemical Biology at Pitt.
"It is not just interesting biology, but it tells us something fundamental about ALT tumors," said O'Sullivan, who is also a member of the Genome Stability Program at UPMC Hillman Cancer Center.
For decades, scientists have understood that DNA is packaged into chromosomes organized into distinct functional regions. At chromosome ends, telomeres protect genetic material, while centromeres act as anchors that ensure chromosomes are properly separated during cell division.
Because of their distinct roles, they have been thought to remain separate, with their strict separation considered essential for maintaining genome stability. The new findings show that this organization can break down in cancer cells, allowing these regions to interact in ways previously thought impossible.
The work focused on a subset of cancers known as ALT+ tumors, which use a mechanism called alternative lengthening of telomeres (ALT) to maintain chromosome ends. This process allows tumor cells to maintain telomere integrity and continue dividing without relying on telomerase, the enzyme most cells use for this function.
Found in approximately 5–10% of cancers overall, ALT occurs in a subset of tumors within several cancer types, including pediatric neuroblastoma, and is often associated with genomic instability, which makes these cancers particularly challenging to treat.
Despite decades of research, however, the specific structural changes in the genome that enable ALT to function have remained unclear—until now.
New genome signature reveals how ALT tumors evolve and survive
In both laboratory models and real tumors, ALT-positive cancers showed higher levels of mixed, or chimeric, centromere and telomere DNA than ALT-negative tumors, supporting the idea that this is a defining feature of these cancers rather than an arbitrary defect.
The study also found that, for ALT+ cells to acquire centromere-like features at their telomeres, they depend on underlying epigenetic changes—alterations in how DNA is packaged and regulated—including the loss of a chromatin regulator called ATRX, which normally helps keep these regions separate. When the researchers disrupted this process, telomeres became unstable and reduced ALT activity.
"It is remarkable that the illegitimate recombination between centromere and telomere sequences, which may begin as a mistake inside the cell, is actually being used by cancer cells to adapt and survive," explains co-corresponding author of the study, Yael Nechemia-Arbely, Ph.D., assistant professor in the Department of Pharmacology and Chemical Biology at Pitt, and a member of the Genome Stability Program at UPMC Hillman Cancer Center.
The findings also point to clinical relevance, particularly for cancers in which ALT is prevalent. The centromere–telomere signature identified in this study offers a potential molecular marker for distinguishing ALT-driven tumors and for better understanding how they progress.
By revealing a structural feature that appears unique to these cancers, the work provides a foundation for identifying patients, monitoring disease evolution, and exploring new therapeutic strategies. As O'Sullivan concluded, "new biology creates new opportunities."
Two fields, one breakthrough
The discovery was enabled by a cross-disciplinary collaboration at UPMC Hillman Cancer Center that brought together scientists studying chromosome regions that, because they do not interact in healthy cells, are rarely studied together.
The researchers initially approached the finding skeptically, but repeated experiments confirmed the interaction, making it impossible to ignore.
The collaboration also required combining complementary techniques. The O'Sullivan lab identified these unexpected centromere–telomere interactions across cell lines and patient tumors using microscopy, sequencing, and biochemical approaches.
The Nechemia-Arbely lab contributed deep expertise in centromere biology and helped map these structures in detail using advanced sequencing methods, including DiMeLo-seq, a cutting-edge approach that revealed distinct centromeric patterns at specific telomeres.
As first author Ragini Bhargava, Ph.D., postdoctoral researcher at the UPMC Hillman Cancer Center describes, "Together, we chose to pursue what seemed like a disruptive finding that led us to discover the potential for a signature for ALT cancers that may one day serve as a diagnostic test for early identification of these cancers."
Publication details
Roderick O'Sullivan, Centromeric footprints preserve telomere integrity in ALT cancers, Nature (2026). DOI: 10.1038/s41586-026-10598-1. www.nature.com/articles/s41586-026-10598-1
Journal information: Nature
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OncologyClinical genetics Provided by University of Pittsburgh Who's behind this story?
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