6/3/2026
Findings in pediatric and adult tumors could lead to a new diagnostic test for a subset of treatment-resistant cancers.
PITTSBURGH — Researchers at the University of Pittsburgh School of Medicine and UPMC Hillman Cancer Center reported June 3, 2026, in Nature that two regions of chromosomes long thought to be permanently separate can merge in a subset of aggressive cancers. The discovery could yield a new diagnostic marker and point toward new treatment strategies, including for children diagnosed with neuroblastoma and other difficult-to-treat pediatric tumors.
The study is the first to identify a structural change in-patient tumor samples in which DNA from centromeres — the grip points where a cell's division machinery latches onto chromosomes — interacts with DNA from telomeres, the protective caps at chromosome ends. This merger creates a molecular signature specific to cancers that rely on a survival mechanism called alternative lengthening of telomeres, or ALT.
ALT allows tumor cells to maintain their chromosome ends and keep dividing indefinitely without telomerase, the enzyme most cells use for that purpose. Found in roughly 5–10% of all cancers, ALT is associated with chromosomal instability — the tendency of cancer cells to accumulate structural errors in their genetic material — and is especially prevalent in pediatric neuroblastoma and certain brain cancers. These tumors are among the hardest to treat.
"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 and a co-leader of the Genome Stability Program at UPMC Hillman Cancer Center. "It is not just interesting biology, it tells us something fundamental about ALT tumors."
A Boundary Cancer Shouldn't Cross
Chromosomes are organized into distinct regions that, in healthy cells, do not intermingle. Telomeres act like the protective plastic tips on shoelaces, preventing chromosome ends from fraying or fusing with neighbors. Centromeres anchor chromosomes during cell division. Because their roles are separate, their strict physical separation has long been considered essential for genetic stability.
The new work shows that separation can break down in ALT-positive cancer cells — and that the breakdown is not random. The centromere–telomere merger depends on loss of a protein called ATRX, which normally keeps these regions apart. ATRX loss is a known hallmark of ALT tumors; this study shows it actively enables the structural change. When the researchers disrupted this process in laboratory models, telomeres became unstable and ALT activity declined.
"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," said co-corresponding author 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.
A Signature That Could Change How Tumors Are Diagnosed
The centromere–telomere signature appeared consistently in ALT-positive cell lines and in actual patient tumors, including pediatric cancers, but not in ALT-negative tumors. For children with neuroblastoma or other ALT-driven pediatric cancers — diseases in which treatment options remain limited — a reliable molecular marker for this mechanism could allow earlier, more precise diagnosis and open pathways to targeted therapy.
The discovery required combining expertise from two research programs that, because centromeres and telomeres are expected not to interact in healthy cells, have rarely been studied together. The O'Sullivan lab mapped centromere–telomere interactions across cell lines and patient tumors using microscopy, sequencing and biochemical methods. The Nechemia-Arbely lab contributed deep expertise in centromere biology and applied an advanced single-molecule sequencing method called DiMeLo-seq — which simultaneously reads DNA sequence and chemical modifications — to map these unusual structures in precise molecular detail.
"Together, we chose to pursue what seemed like a disruptive finding — one that could lead to a diagnostic test for the early identification of these cancers," said first author Ragini Bhargava, Ph.D., a postdoctoral researcher at UPMC Hillman Cancer Center.
The research team's next steps include validating the centromere–telomere signature in larger patient tumor cohorts through UPMC Hillman Cancer Center, where Pitt researchers and UPMC clinicians work in close collaboration to move laboratory discoveries toward clinical application. O'Sullivan said the findings open new possibilities. "New biology creates new opportunities," he said.
Frequently Asked Questions
Q: What are ALT-positive cancers, and why are they so hard to treat?
A: ALT-positive cancers use a backup mechanism — alternative lengthening of telomeres — to maintain their chromosome ends and keep dividing, bypassing the enzyme telomerase that most cells rely on. This makes them genetically unstable and resistant to many standard treatments. They account for roughly 5–10% of all cancers and are common in certain pediatric tumors.
Q: What did researchers actually find, and why does it matter?
A: For the first time, researchers documented centromere DNA — normally located at the center of chromosomes — inserted near telomeres at chromosome ends in patient tumor samples. This structural signature appears unique to ALT-positive cancers and could serve as a molecular marker to identify and monitor these tumors earlier and more precisely.
Q: Could this discovery lead to new treatments?
A: Potentially, yes. The study found that the centromere–telomere merger depends on loss of a protein called ATRX. When researchers disrupted that process in the lab, ALT activity declined. This suggests the pathway could be a therapeutic target, and the research team plans to validate the signature in larger patient cohorts at UPMC Hillman Cancer Center as a step toward clinical application.
Additional Resources
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Published study: Genomic and Epigenomic Centromeric Footprints Preserve Telomere Integrity in ALT Cancers
- EurekAlert! release: University of Pittsburgh researchers discover unexpected chromosome interaction that fuels aggressive cancers
Authors and Funding
Authors: Additional authors on the study are Megan Mahlke, Ph.D., Baylee Smith, Katherine Ramsey, Takoda Zuehlke, Wesley Bowman II, Ph.D., Michelle Lynskey, Ph.D., Anne Wondisford, Ph.D., Jean-Baptiste Ouriou, Sandra Schamus-Hayes, Michael Calderon, Simon Watkins, Ph.D., Jennifer Bone, Ph.D., Alok Joglekar, Ph.D. from the University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, or both. Tobias Schmidt, Ph.D., A. Williams, Ph.D., and Jan Karlseder, Ph.D., from the Salk Institute for Biological Studies; Christoph Bartenhagen, Ph.D., and Matthias Fischer, Ph.D. from the University of Cologne and the Center for Molecular Medicine Cologne, Germany.
Funding and Disclosures: Funding for this study was provided by the National Cancer Institute ( R01CA207209, R01262316, P30CA047904, F30CA278287, DP2AI176138), The National Institute of General Medical Sciences (R35GM142717), the German Research Foundation (SFB1399 (413326622), SFB1588 (493872418), FI 1926/1-1, and FI 1926/2-1) and the "Netzwerke 2021" program of the Ministry of Culture and Science of North Rhine-Westphalia for the CANTAR project.
