Research led by Memorial Sloan Kettering Cancer Center (MSK) is shedding new light on how ovarian cancer evolves \u2014 insights that could help researchers develop more effective treatment strategies.<\/p>\n
While ovarian cancer diagnoses and deaths have\u00a0decreased over recent decades<\/a>, 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.<\/p>\n A new study,\u00a0published July 16 in\u00a0Nature<\/a>, used single-cell sequencing and other techniques to examine a phenomenon known as \u201cwhole-genome doubling\u201d in high-grade serous ovarian carcinoma (HGSOC), the most common and aggressive form of\u00a0ovarian cancer<\/a>.<\/p>\n Whole-genome doubling (WGD) is a process in which all of the chromosomes in a cancer cell\u2019s genome are duplicated, which can help the cancer cells become stronger and more adaptable, and therefore more resistant to treatments.<\/p>\n \u201cThe 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 \u2014 in ovarian cancer, we observe WGD in the more advanced, difficult-to-treat cancers,\u201d says MSK\u00a0computational oncologist Andrew McPherson, PhD<\/a>, a lead author of the study.<\/p>\n The study, which was overseen by senior author\u00a0Sohrab Shah, PhD<\/a>, Chief of MSK\u2019s 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\u2019s normal immune response.<\/p>\n \u201cOur findings expand our understanding of ovarian cancer and stress the importance of considering whole-genome doubling in future treatment strategies,\u201d says Dr. Shah, who is also the Nicholls-Biondi Chair at MSK. \u201cThis might include drugs that specifically target WGD as well as developing a better understanding of how WGD affects responses to our current treatments.\u201d<\/p>\n WGD-high tumors suppress immune responses<\/p>\n 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.<\/p>\n In order to study WGD\u2019s 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.<\/p>\n The researchers analyzed more than 30,000 cells \u2014 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.<\/p>\n \u201cAfter a cell experiences this doubling, we can see that there\u2019s a profound increase in lost chromosomes and other molecular changes,\u201d Dr. Shah says. \u201cIn these cells, we could see a higher rate of micronuclei \u2014 small, extra nuclei with fragments of DNA in them, which is an indication of what we call \u2018chromosomal instability.\u2019 These micronuclei often rupture, spilling DNA into the cells in a way that should set off alarm bells for the innate immune system.\u201d<\/p>\n But the study revealed that the WGD-high tumors develop ways to dampen immune responses, despite their high levels of instability \u2014 such as by repressing the STING pathway, which would normally activate immune cells to fight the cancer.<\/p>\n \u201cSurprisingly, we found WGD-low tumors are actually more visible to the immune system and more likely to trigger an inflammatory immune response,\u201d Dr. McPherson adds.<\/p>\n Mapping genome doubling in HGSOC sheds light on tumor evolution<\/p>\n Mapping the doubling of genomes through single-cell sequencing also revealed new details about the evolution of ovarian cancer tumors.<\/p>\n \u201cThe technique we developed allowed us to study how these tumors evolve,\u201d Dr. McPherson says. \u201cWe were able to place the WGD events within the context of the evolutionary tree and say whether they\u2019re on the trunk of the tree or how far along a branch they happen.\u201d<\/p>\n One of the key findings from the study was that WGD is an\u00a0ongoing\u00a0process. 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.<\/p>\n The study points to the need for additional research to understand how small environmental changes in the fallopian tubes \u2014 where high-grade serous ovarian cancer is believed to often originate \u2014 might influence the initiation of WGD events, Dr. McPherson notes.<\/p>\n Collaboration was key<\/p>\n 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\u00a0Chief of Gynecologic Medical Oncology Carol Aghajanian, MD<\/a>, and\u00a0Chief of Gynecology Surgery Nadeem Abu-Rustum, MD<\/a>, Dr. Shah says.\u00a0Britta\u202fWeigelt,\u202fPhD<\/a>\u00a0and her lab were also vital to the project, collecting and reviewing tissue samples and processing them for sequencing.\u00a0<\/p>\n \u201cFrom identifying patients to collecting samples to analyzing them, it was truly a team effort,\u201d Dr. Shah says.<\/p>\n 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\u00a0Neeman Mohibullah, PhD<\/a>, and her single-cell team at MSK\u2019s\u00a0Integrative Genomics Operations<\/a>\u00a0sequencing core.<\/p>\n Several external collaborators were also integral to the project.<\/p>\n The study was part of a broader initiative called\u00a0MSK SPECTRUM,<\/a>\u00a0a multidisciplinary effort to harness MSK\u2019s computational expertise to study ovarian cancer evolution, treatment, and response. The current study builds on previous research from the project that also was\u00a0published in\u00a0Nature<\/a>.<\/p>\n Reference: McPherson A, V\u00e1zquez-Garc\u00eda I, Myers MA, et al. Ongoing genome doubling shapes evolvability and immunity in ovarian cancer. Nature. 2025:1-10. doi:\u00a010.1038\/s41586-025-09240-3<\/a><\/p>\n This article has been republished from the following materials<\/a>. Note: material may have been edited for length and content. For further information, please contact the cited source. Our press release publishing policy can be accessed here<\/a>.<\/p>\n","protected":false},"excerpt":{"rendered":"Research led by Memorial Sloan Kettering Cancer Center (MSK) is shedding new light on how ovarian cancer evolves…\n","protected":false},"author":2,"featured_media":15990,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[50],"tags":[200,79],"class_list":["post-15989","post","type-post","status-publish","format-standard","has-post-thumbnail","category-genetics","tag-genetics","tag-science"],"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/posts\/15989","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/comments?post=15989"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/posts\/15989\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/media\/15990"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/media?parent=15989"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/categories?post=15989"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/us\/wp-json\/wp\/v2\/tags?post=15989"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}