Genetic Signature for Aggressive Tumors: New Study

14 July 2026

Genetic Signature for Aggressive Tumors: The Discovery on Telomeres and Centromeres

Researchers at the University of Pittsburgh and the UPMC Hillman Cancer Center have discovered an unexpected chromosomal interaction that could explain how some aggressive tumors are able to grow without limits. The study, published in Nature, identifies a previously unknown biological mechanism that characterizes a subgroup of cancers that are particularly difficult to treat.

The Chromosome That Breaks the Rules

For decades, scientists have known that DNA is organized into chromosomes divided into distinct functional regions. At the ends of the chromosome, telomeres protect genetic material; at the center, centromeres act as anchors that ensure proper chromosome separation during cell division. Their separation has long been considered essential for maintaining genome stability.

According to Roderick O'Sullivan, senior author of the study and professor in the Department of Pharmacology and Chemical Biology at the University of Pittsburgh, this organization can break down in cancer cells. The research shows that these two chromosome components — whose isolation was believed to be absolute — can interact in ways previously thought impossible in ALT-positive (ALT+) tumors.

The ALT Mechanism and the Tumor Signature

ALT+ tumors represent about 5–10% of all cancers, but they are particularly common in certain tumor types, such as pediatric neuroblastoma. These tumors use a mechanism called alternative lengthening of telomeres (ALT) to maintain the integrity of chromosome ends and continue dividing without relying on telomerase — the enzyme most normal cells use for this function.
Until now, however, the specific structural changes in the genome that allow the ALT mechanism to function had not been clarified.

The study demonstrated that ALT+ tumors accumulate higher levels of mixed, or chimeric, DNA derived from centromeres and telomeres compared to ALT-negative tumors. This feature is not a random defect but a defining characteristic of these cancers.

To acquire this genetic signature, tumor cells undergo epigenetic changes — alterations in how DNA is packaged and regulated — including the loss of a regulatory protein called ATRX, which normally keeps these two chromosomal regions separate. When researchers disrupted this process, telomeres became unstable and ALT activity decreased.

An Error That Becomes an Advantage

According to Yael Nechemia-Arbely, co-corresponding author of the study and assistant professor in the Department of Pharmacology and Chemical Biology at the University of Pittsburgh, this phenomenon has deep biological significance. Illegitimate recombination between centromere and telomere sequences, likely beginning as a cellular error, is exploited by tumor cells to adapt and survive. This ability to turn a genetic anomaly into a survival tool is what makes these tumors particularly aggressive.

Clinical Implications and Towards New Therapies

This discovery has significant clinical relevance, especially for tumors in which the ALT mechanism is prevalent. The centromere–telomere signature identified in the study offers a potential molecular marker to distinguish ALT-driven tumors and better understand how they progress over time. By revealing a structural feature that appears unique to these cancers, the research provides a strong foundation for identifying at-risk patients, monitoring disease evolution, and exploring new therapeutic strategies.

An Interdisciplinary Collaboration

The study was made possible by a cross-disciplinary collaboration at the UPMC Hillman Cancer Center, bringing together scientists specialized in chromosomal regions that, due to their lack of interaction in healthy cells, are rarely studied together.

O'Sullivan’s lab identified these unexpected centromere–telomere interactions through microscopy, sequencing, and biochemical approaches. Nechemia-Arbely’s 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.

Ragini Bhargava, a postdoctoral researcher at the UPMC Hillman Cancer Center and first author of the study, described the process as choosing to pursue evidence that initially appeared disruptive. This decision led to the discovery of a potential signature for ALT tumors that could one day serve as a diagnostic test for early identification of these cancers and, consequently, enable access to targeted therapeutic strategies.

Read the press release: University of Pittsburgh Researchers Discover Unexpected Chromosome Interaction That Fuels Aggressive Cancers