Study provides new insights into the genetic complexity of cancer metastasis

When cancer spreads from a primary tumor to new sites throughout the body, it undergoes changes that increase its genetic complexity.

A new study from researchers at Memorial Sloan Kettering Cancer Center (MSK) and Weill Cornell Medicine provides fresh insights about how cancers evolve when they metastasize — insights that could aid in developing strategies to improve the effectiveness of treatment.

The team — led by collaborators Luc Morris, MD, a surgeon and cancer genetics research lab director at MSK, Xi Kathy Zhou, PhD, a professor of research in population health sciences at Weill Cornell Medicine, and Chaitanya Bandlamudi, PhD, a cancer genomics researcher at MSK — examined the genomic profiles of more than 3,700 patients across 24 cancer types who had multiple tumor sites biopsied over time.

The samples were profiled using the MSK-IMPACT^® tumor sequencing test. MSK-IMPACT is the foundation of MSK’s clinical precision oncology enterprise, which has performed genomic profiling of 100,000 patients as part of their clinical care. This has created a uniquely valuable collection of data, and it allowed the research team to compare the genetic profiles of an initial tumor and metastatic site from the same patient.

Metastatic Tumors Harbor More Copy-Number Alterations

The team’s findings, which were published June 2 in Nature Genetics, showed that tumors evolve over time, and that metastases tend to accumulate more copy-number alterations (CNAs) than mutations. This led the researchers to wonder why CNAs, but not mutations, were so commonly emerging when tumors metastasized.

Mutations are like small typos in the genetic code that can affect how a gene functions, leading to the production of abnormal proteins or the alteration of gene expression. CNAs, on the other hand, are larger scale duplications or deletions of genetic material. 

One extreme form of CNA — genome doubling — turned out to be important during the process of metastasis.

“We found that whole-genome duplication — which is the doubling of the entire set of chromosomes in a cancer cell — was the most common genetic event during metastasis, occurring in nearly one-third of patients,” explains study first author Karena Zhao, MD, who conducted research at MSK while attending medical school at Weill Cornell Medical College.

As cancer cells divide and make mistakes in replicating their DNA, mutations accumulate. Some mutations help the cells grow faster, while other mutations can affect essential genes and be harmful to the cell. 

“Genome doubling allows cancer cells to hedge their bets, creating additional copies of genes, so that one copy can be mutated or deleted, while the other copy survives intact,” Dr. Zhou adds. “This enhances the tumor cell’s ability to adapt, survive, and resist treatments.”

Understanding Genomic Differences Between Primary and Metastatic Tumors Is Critical 

Unlike CNAs, more mutations can actually make tumors more visible to the immune system. That’s because the changes to their genetic sequences can make them produce abnormal proteins, which are then treated like a foreign threat by the immune system. The team found that CNAs made tumors resistant, while mutations made tumors more susceptible to immunotherapy.

“In the end, our study found that during metastasis, cancer cells tend to evolve by maximizing CNAs, while not generating too many mutations that could potentially stimulate an immune response,” Dr. Bandlamudi says.

Together, the findings suggest that newer strategies, such as therapies to target genetic instability in these highly altered cells or to alter the tumor microenvironment, could be critical for creating lasting responses in metastatic cancer, the researchers say.

“Understanding these key genomic differences between primary and metastatic tumors is vital for clinical care, as biomarkers like CNAs and tumor mutational burden are increasingly used by clinicians to inform decision-making, especially around the use of immunotherapy drugs,” Dr. Morris says.

Additional Authors, Funding, and Disclosures

Additional authors of the study include Joris Vos, Stanley Lam, Lillian Boe, Daniel Muldoon, Catherine Han, Cristina Valero, Mark Lee, Conall Fitzgerald, Andrew Lee, Manu Prasad, Swati Jain, Xinzhu Deng, Timothy Chan, and Michael Berger.

This study was supported by the Department of Defense Peer Reviewed Cancer Research Program and Rare Cancer Research Program; The Geoffrey Beene Cancer Research Center; Cycle for Survival: Team Fearless4Jen; The Jayme Flowers Fund; The Larry De Shon Fund; The Raquel and Riccardo Di Capua Fund; the Weill Cornell Clinical and Translational Science Center Grant (2UL1-TR-002384), the Area of Concentration Program at Weill Cornell Medical College; and the National Cancer Instiute (P30 CA008748).

Several of the authors report financial and advisory relationships with biotech and pharmaceutical companies. Please refer to the full study for details.

Read the study: Longitudinal and multisite sampling reveals mutational and copy number evolution in tumors during metastatic dissemination, Nature Genetics. DOI: 10.1038/s41588-025-02204-3