Research led by Memorial Sloan Kettering Cancer Center (MSK) is shedding new light on how ovarian cancer evolves — insights that could help researchers develop more effective treatment strategies.
While ovarian cancer diagnoses and deaths have decreased over recent decades , the disease remains a leading cause of cancer-related death in women. This is largely because the cancer often spreads at a microscopic level within the abdomen early on, resulting in diagnosis at an advanced stage when treatment is less effective.
A new study, published July 16 in Nature , used single-cell sequencing and other techniques to examine a phenomenon known as "whole-genome doubling" in high-grade serous ovarian carcinoma (HGSOC), the most common and aggressive form of ovarian cancer .
Whole-genome doubling (WGD) is a process in which all of the chromosomes in a cancer cell's genome are duplicated, which can help the cancer cells become stronger and more adaptable, and therefore more resistant to treatments.
"The paradox of WGD is that it can be both a driver and a barrier to cancer progression, depending on the context and timing of the event — in ovarian cancer, we observe WGD in the more advanced, difficult-to-treat cancers," says MSK computational oncologist Andrew McPherson, PhD , a lead author of the study.
The study, which was overseen by senior author Sohrab Shah, PhD , Chief of MSK's Computational Oncology Service and Director of the Halvorsen Center for Computational Oncology, found that more than 65% of the ovarian cancer tumors they studied had a high level of whole-genome doubling and that these tumors were better able to suppress the patient's normal immune response.
"Our findings expand our understanding of ovarian cancer and stress the importance of considering whole-genome doubling in future treatment strategies," says Dr. Shah, who is also the Nicholls-Biondi Chair at MSK. "This might include drugs that specifically target WGD as well as developing a better understanding of how WGD affects responses to our current treatments."
WGD-High Tumors Suppress Immune Responses
Whole-genome doubling happens in more than 30% of solid cancers and is known to lead to increased rates of metastasis and drug resistance, as well as to poorer clinical outcomes.
In order to study WGD's impact on ovarian cancer in a nuanced way, the researchers used a technique called Direct Library Preparation (DLP) single-cell sequencing, which allowed them to look at differences between tens of thousands of individual cells. DLP sequencing revealed key subpopulations of cells that would otherwise get lost in bulk sequencing.
The researchers analyzed more than 30,000 cells — representing 70 tumor samples from 41 patients with ovarian cancer who had not yet received any treatment. They categorized 66% of the tumors as WGD-high, meaning more than 8 out of 10 cells in a sample had undergone at least one instance of genome doubling.
"After a cell experiences this doubling, we can see that there's a profound increase in lost chromosomes and other molecular changes," Dr. Shah says. "In these cells, we could see a higher rate of micronuclei — small, extra nuclei with fragments of DNA in them, which is an indication of what we call 'chromosomal instability.' These micronuclei often rupture, spilling DNA into the cells in a way that should set off alarm bells for the innate immune system."
But the study revealed that the WGD-high tumors develop ways to dampen immune responses, despite their high levels of instability — such as by repressing the STING pathway, which would normally activate immune cells to fight the cancer.
"Surprisingly, we found WGD-low tumors are actually more visible to the immune system and more likely to trigger an inflammatory immune response," Dr. McPherson adds.
Mapping Genome Doubling in HGSOC Sheds Light on Tumor Evolution
Mapping the doubling of genomes through single-cell sequencing also revealed new details about the evolution of ovarian cancer tumors.
"The technique we developed allowed us to study how these tumors evolve," Dr. McPherson says. "We were able to place the WGD events within the context of the evolutionary tree and say whether they're on the trunk of the tree or how far along a branch they happen."
One of the key findings from the study was that WGD is an ongoing process. It can happen early in the development of a tumor or later in smaller groups of cancer cells. It can also happen multiple times in the same tumor.
The study points to the need for additional research to understand how small environmental changes in the fallopian tubes — where high-grade serous ovarian cancer is believed to often originate — might influence the initiation of WGD events, Dr. McPherson notes.
Collaboration Was Key
The study would not have been possible without extensive collaboration and teamwork between computational researchers and the surgeons, pathologists, and oncologists at MSK who specialize in gynecologic cancers, led by Chief of Gynecologic Medical Oncology Carol Aghajanian, MD , and Chief of Gynecology Surgery Nadeem Abu-Rustum, MD , Dr. Shah says. Britta Weigelt, PhD and her lab were also vital to the project, collecting and reviewing tissue samples and processing them for sequencing.
"From identifying patients to collecting samples to analyzing them, it was truly a team effort," Dr. Shah says.
In addition, DLP sequencing is an especially difficult protocol to implement and required a team of technicians working long hours to complete each experiment, Dr. McPherson adds, noting the project would not have been possible without the dedication and expertise of Neeman Mohibullah, PhD , and her single-cell team at MSK's Integrative Genomics Operations sequencing core.
Several external collaborators were also integral to the project.
The study was part of a broader initiative called MSK SPECTRUM, a multidisciplinary effort to harness MSK's computational expertise to study ovarian cancer evolution, treatment, and response. The current study builds on previous research from the project that also was published in Nature .
Additional Authors, Funding, and Disclosures
The study had 58 authors — please refer to the journal article for the full list. Along with Dr. McPherson, the study's co-first authors included: Ignacio Vázquez-García, PhD, Matthew Myers, PhD, Duaa Al-Rawi, MD, PhD, and Matthew Zatzman, PhD.
The research was primarily supported through a Department of Defense Congressionally Directed Medical Research Program award (W81XWH-20-1-0565), an Ovarian Cancer Research Alliance Collaborative Research Development Grant (648007), the National Institutes of Health (R01 CA281928-01), and by the Seidenberg Family Foundation. Additional support was provided by the Halvorsen Center for Computational Oncology, Cycle for Survival supporting Memorial Sloan Kettering Cancer Center, and Cancer Research UK. Please refer to the journal article for a full list of acknowledgements.
Dr. Shah reports receiving research funding from AstraZeneca and Bristol Myers Squibb, unrelated to the current project. Please refer to the journal article for a full list of author disclosures.
Read the paper: " Ongoing Genome Doubling Shapes Evolvability and Immunity in Ovarian Cancer ," Nature. DOI: 10.1038/s41586-025-09240-3.
