image: An MSK reseacher working in the lab.
Credit: Memorial Sloan Kettering Cancer Center
New research from Memorial Sloan Kettering Cancer Center (MSK) uncovers clues about how cells control a key DNA repair protein; develops a new method for studying gene amplifications in cancer; sheds new light on tumor suppressor genes; shows MSK-IMPACT® could be used for HLA genotype screening to predict response to cellular therapies; identifies a possible strategy to overcome immune evasion in ovarian cancer; and finds strong support for telemedicine visits among cancer patients.
Uncovering new clues about how cells control a key DNA repair protein
A major safeguard against cancer is the ability of a cell to accurately repair DNA damage. However, during the lifetime of a cell, DNA damage provides a constant challenge to keeping our inherited genes intact. A particularly harmful kind of DNA damage occurs when both strands of DNA are broken. The protein RAD51 is a central player in repairing this damage — through a process called homologous recombination. RAD51 coordinates the association of damaged DNA with identical sequences to facilitate restoration of genetic material that has been damaged. But how RAD51 is controlled during this dynamic process, including how it detaches from DNA after it has finished its job, is not completely understood.
A new study from developmental biologist Maria Jasin, PhD, and postdoctoral fellow Tai-Yuan Yu, PhD, together with the lab of structural biologist Xiaodong Zhang, PhD, at Imperial College London, took a closer look at this question by focusing on a protein called FIGNL1 that associates with RAD51. By probing the genetic dependencies between RAD51 and FIGNL1 in mouse embryonic cells, they found that FIGNL1 is essential for removing RAD51 from chromosomes. Tweaking the level of RAD51 by reducing it by half led to viability of both cells and mouse embryos. Insights into RAD51-FIGNL1 protein interactions using cryo-electron microscopy led to the discovery that FIGNL1 dismantles RAD51 from DNA by pulling it through a hole in the FIGNL1 protein complex. Because RAD51 associates with important tumor suppressors like BRCA2, this research identifies the control of RAD51 as an important mechanism for cell proliferation in the context of cancer.
Read more in Science.
A new method for studying gene amplifications in cancer
Gene amplifications, in which certain genes are duplicated multiple times, are common in cancer and can drive tumor growth. Recreating these amplifications in the lab, however, has proved challenging. Now an MSK-led team — led by co-first authors Davide Pradella, PhD, Minsi Zhang, MD, PhD, Rui Gao, PhD, and Melissa A. Yao, and overseen by senior author Andrea Ventura, MD, PhD — has developed a new method to study gene amplifications in cancer by engineering them in cells and mice using extrachromosomal DNAs (ecDNAs). EcDNAs are small circular DNA molecules that exist outside of the main chromosomal DNA. In a mouse model of liver cancer, ecDNAs with oncogene amplifications accumulated in cells, leading to the development of tumors, the scientists found. The research provides insight into the role of gene amplifications in cancer and may help identify new targets for cancer therapies. “We hope the tools and the genetically engineered mouse models we developed will help the scientific community to answer important questions about the biology of ecDNAs and their role in cancer,” Dr. Ventura says. Read more in Nature.
MSK research sheds new light on loss of tumor suppressor genes
Tumor suppressor genes (TSGs) play critically important roles in preventing uncontrolled cell growth and maintaining genomic stability. Loss of function mutations that reduce or eliminate normal activity in TSGs are ubiquitous in cancers. A widely accepted idea — known as Knudson’s two-hit hypothesis — postulates that both copies of a tumor suppressor gene, one inherited from each parent, must be compromised (biallelic inactivation) in order for cancer to develop.
Now, a team of researchers at MSK found that biallelic inactivation is not universal among the majority of TSGs. Overseen by study senior authors Chaitanya Bandlamudi, PhD, and Ed Reznik, PhD, the researchers conducted a comprehensive analysis of 224 TSGs in more than 48,000 cancer patients. They found that some TSGs showed high rates of biallelic inactivation in all cancers where they were mutated; inactivation patterns in other TSGs depended on the type of cancer. Additionally, some TSGs were predominantly inactivated with the loss of just one copy of the gene.
In some contexts, whether the patient lost one copy (monoallelic) or both copies (biallelic) of a TSG had important prognostic and treatment implications. For example, in KEAP1 mutated lung cancers, only the patients with biallelic but not monoallelic KEAP1 loss had significantly worse outcomes on standard of care treatments.
The study, which was led by co-first authors Mark Zucker, PhD, and Maria Perry, MS, also explored a multitude of ways in which the signals for selection for biallelic inactivation can be leveraged to highlight genetic alterations that occur later in the development and progression of a tumor — for example, Wnt pathway alterations in lung and prostate cancers — or for enabling reclassification of variants of unknown biological significance, as with KEAP1.
Overall, the findings show that the number of functional gene copies is a fundamental factor that influences disease development and response to treatment. And that understanding the gene copy status of TSGs could provide valuable insights for personalizing treatment strategies. Read more in Cell.
Next-generation sequencing for HLA genotype screening and matching to HLA-restricted therapies
The first human leukocyte antigen (HLA)-restricted therapies were recently approved by the U.S. Food and Drug Administration (FDA) for certain cancers including the T cell receptor therapies tebentafusp and afami-cel, based on studies led by MSK’s Alexander Shoushtari, MD, and Sandra D’Angelo, MD. However, HLA genotyping is not currently assessed in routine next-generation sequencing panels that match patients with precision therapies.
HLA genotyping looks at genes that encode cell-surface proteins responsible for regulating the immune system. It is often used to match a transplant recipient with a compatible donor — and it is increasingly being used to predict individuals’ response to cellular therapies.
Now a new study by Michael Gormally, MD, PhD, Monica Chen, MD, Mark Donoghue, PhD, Adam Schoenfeld, MD, and their team investigated whether HLA genotypes could be determined using information captured through MSK’s next-generation sequencing test MSK-IMPACT®. The researchers analyzed nearly 60,000 patients — the largest cohort of cancer patients to date — who underwent MSK-IMPACT testing to look at their HLA class I genotypes.
For a large subset of patients who had also undergone separate CLIA-certified HLA genotyping, the investigational MSK-IMPACT HLA genotype was a near perfect match. The team also found that incorporating HLA genotyping via MSK-IMPACT significantly increased the number of patients eligible for HLA-restricted therapy trials and streamlined the process of matching patients to the right trial. The investigators aim to expand this capability to HLA class II genotypes. And they plan to complete a formal validation to incorporate the HLA genotyping into future versions of MSK-IMPACT. Read more in JAMA Oncology.
Possible strategy to overcome immune evasion in ovarian cancer
Traditional biomarkers to predict response to immune checkpoint inhibitors, such as tumor mutational burden and PD-L1 expression, have limited predictive value for ovarian cancer. Now a multi-institution team — overseen by senior authors Britta Weigelt, PhD, and Dmitriy Zamarin, MD, PhD (now at the Icahn School of Medicine), and led by former Weigelt Lab postdoc Melica Brodeur, MD (now at McGill University) — has identified a chromatin remodeling complex as a potential target to overcome immune evasion in ovarian cancer. The study shows that removing SMARCA4 from mouse models of ovarian cancer led to improved infiltration and activation of immune cells in the tumor microenvironment. Additionally, treatment with an inhibitor of the BRG1 protein (encoded by SMARCA4) replicated the effects seen in the genetically engineered mouse models. The findings suggest that targeting SMARCA4 could potentially improve the efficacy of immunotherapy in ovarian cancer. Further evaluation of SMARCA4 mutations as predictors of immunotherapy response and the use of SMARCA4/BRG1 as a therapeutic target is warranted, the authors report. Read more in Science Advances.
Most cancer patients like telemedicine visits, survey finds
Nearly 3 in 4 cancer patients rated their first telemedicine visit as good as or better than an in-patient visit, a survey of more than 27,000 users at MSK from 2020 to 2023 found. And nearly 20% rated the option as superior to an in-person visit.
While the use of telemedicine was widely adopted in response to the COVID-19 pandemic, patients’ experiences are poorly understood. And the policy and payment landscape of telemedicine visits in cancer care delivery remains uncertain.
“Our findings suggest that patients see great value in telemedicine visits, and that health care systems should continue to integrate them into cancer care and work to improve remaining technical challenges and barriers to adoption,” says MSK medical oncology / hematology fellow Sahil Doshi, MD, who led the research.
Read more in JAMA Network Open.