About 1 in 5 patients with cancer who undergo genetic testing are incidentally found to have mutations in their blood called clonal hematopoiesis of indeterminate potential (CHIP). A study from Vanderbilt Health researchers reveals that it puts them at increased risk for heart disease following cancer treatment.

The findings, published Jan. 8 in JAMA Oncology, support the potential benefits of screening patients for CHIP before they undergo cancer treatment so they can be more closely monitored for heart complications. CHIP is a condition, not a disease, characterized by age-related variants in blood stem cells, and it is typically asymptomatic.

The researchers were able to determine which patients had CHIP by using Vanderbilt Health’s biorepository, BioVU, to link electronic health records with whole-genome sequencing data. They compared the cardiovascular health outcomes of the patients with CHIP to outcomes of patients without the condition. All the patients had been diagnosed with solid tumors, and none had heart failure, ischemic heart disease or arrhythmia before undergoing cancer treatment.

Over a 10-year period following treatment, patients with CHIP had a significantly higher incidence of heart failure (20.3% versus 14.5%) and ischemic cardiovascular disease (25.3% versus 18.5%). The effect was amplified in patients who received more intensive chemotherapy.

“We frequently find CHIP in patients with cancer, but previously we did not consider this to be an important result for their care. We now know that these patients are at higher risk of heart disease and would likely benefit from including cardiologists in their care team,” said the study’s corresponding author, Alexander Bick, MD, PhD, associate professor of Medicine, holder of the Edward Claiborne Stahlman Chair, and director of the Division of Genetic Medicine and Clinical Pharmacology.

The patients received chemotherapy, radiotherapy, immunotherapy, or a combination of the treatments. Cardiovascular disease is the leading cause of noncancer deaths among cancer survivors.

The researchers analyzed data from 8,004 patients, and 549 of them were identified with CHIP. To their knowledge, the study is the largest to date evaluating the association between CHIP and cardiovascular disease in patients with solid tumors who underwent cancer treatment. Most patients with CHIP were male (54% versus 45%) and had hypertension (78% versus 69%) compared to patients without the condition.

The clinical implications of the study are that there may be value in testing patients for CHIP prior to cancer treatment to stratify risk and tailor monitoring for cardiovascular diseases and offering early cardio-oncology consultations as well as consideration of cardioprotective strategies.  

The researchers received support from the National Institutes of Health (grants DP5OD029586 and T32GM007347). The sequencing of 250,000 individuals who have donated samples to BioVU has been funded by the Alliance for Genomic Discovery.

The study’s first authors are Derek Shyr, PhD, and Yash Pershad. The study was jointly supervised by Bick and Leo Luo, MD, assistant professor of Radiation Oncology at Vanderbilt Health.

Other Vanderbilt Health authors on the study are Ashwin Kishtagari, MD, Robert Corty, MD, PhD, Eric Shinohara, MD, MSCI, Ben Ho Park, MD, PhD, and Brett Heimlich, MD, PhD.

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A multi-institutional research team that included genomic scientists from Vanderbilt Health has identified a potential target for blood cancer prevention and treatment.

Their report, published Jan. 1 in the journal Science, could lead to new treatments for blood cancers, which kill an estimated 23,540 people in the United States every year.

The research team, led by scientists from Boston Children’s Hospital, Dana-Farber Cancer Institute, the Broad Institute of MIT and Harvard, and Memorial Sloan Kettering Cancer Center, found that the protein Musashi-2 (MSI2) is essential for the function of blood-forming stem cells.

High levels of MSI2 can support the unchecked growth of abnormal stem cells, a precancerous condition known as clonal hematopoiesis of indeterminate potential, or CHIP.

The researchers used a genome-wide association study (GWAS) meta-analysis to identify a haplotype, or inherited grouping of genomic variants, which reduces MSI2 expression, thereby protecting against CHIP.

To validate these findings in humans, Alexander Bick, MD, PhD, Yash Pershad, and colleagues leveraged Vanderbilt Health’s DNA biobank, BioVU, the world’s largest repository of genetic material linked to de-identified electronic health records based at a single academic center.

By analyzing a unique longitudinal cohort of 3,000 patients with genetic sequencing performed approximately six years apart, the Vanderbilt Health team tested whether a variant which reduced the expression of MSI2 protected against the expansion of precancerous mutations.

Patients who carried the protective variant had precancerous clones that grew significantly more slowly than those without the variant. In many of these patients, the abnormal cells were transient; that is, they disappeared entirely over the study period rather than expanding into cancer.

“Most genetic studies only provide information from a snapshot in time, but the longitudinal samples in BioVU allowed us to study the mutations over six years,” noted Pershad, an MD/PhD student in the Bick lab, who with Bick is among the paper’s co-authors.

“We could clearly see that in people with the protective variant, precancerous clones behaved fundamentally differently than we expected — they shrunk or disappeared rather than expanding and becoming cancer,” Pershad said.

While CHIP results from somatic (acquired) blood stem cell mutations, this protection against it is inherited. This human genetic evidence suggests a potential way to prevent blood cancer by targeting MSI2 through small molecule inhibition or genome editing.

“More broadly,” the researchers concluded, “we provide an example of how resilience to cancer can arise through inherited genetic variation, motivating the search for other natural pathways that could be leveraged to prevent or treat malignancy.”

Bick, the Edward Claiborne Stahlman Professor, associate professor of Medicine, and director of the Division of Genetic Medicine and Clinical Pharmacology at Vanderbilt Health, is internationally known for his research on the genetics of blood disorders.

His research is supported in part by National Institutes of Health grants DP5OD029586, R01AG088657 and R01AG083736, a Burroughs Wellcome Fund Career Award, a Pew-Stewart Scholar for Cancer Research award, and a Hevolution/AFAR New Investigator Award in Aging Biology and Geroscience Research.

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One person in 10 over the age of 70 will experience an explosive, clonal growth of abnormal blood cells, called clonal hematopoiesis of indeterminant potential or CHIP, that increases the risk of blood cancer and death from cardiovascular, lung and liver disease. 

The risk of blood cancer differs significantly, however, depending upon whether patients with CHIP also develop cytopenia (low blood cell count). 

An analysis of genetic sequencing data from more than 34,000 people over a 17-year period by researchers at Vanderbilt University Medical Center has found that persistent cytopenia appears to be a critical step in the progression of CHIP to blood cancer. 

For patients with CHIP who developed cytopenia, the risk of progression to blood cancer was 10 times higher than it was for patients without cytopenia — a 1-in-200 chance per year versus 1 in 2,000, the researchers report in the June 2025 issue of the Lancet journal, eClinicalMedicine.  

These findings suggest that checking blood counts regularly may be an effective way to monitor patients with CHIP for their risk of developing blood cancer, and cytopenia-free survival may be a valuable endpoint for clinical trials aimed at preventing blood cancer in these patients.

“This work is the largest longitudinal analysis of its kind and provides a roadmap for identifying high-risk CHIP patients who may benefit from closer monitoring or early intervention,” said the paper’s corresponding author, Alexander Bick, MD, PhD, associate professor of Medicine and director of the Division of Genetic Medicine at VUMC. 

“It also lays the groundwork for more feasible and targeted clinical trials in blood cancer prevention,” he said. 

Bick is internationally known for his research on the genetics of blood disorders. He and his colleagues have advanced the understanding of somatic (non-inherited) mutations in blood stem cells that can trigger a potentially life-threatening clonal growth of abnormal cells known as CHIP.  

Blood cancer (myeloid neoplasm) results from the abnormal growth of myeloid (blood) cells in the bone marrow. The current study compared blood cancer rates in patients with CHIP who did not develop cytopenia, to those with both CHIP and concurrent, clonal cytopenia of undetermined significance. 

Led by the paper’s first authors, James Brogan, MD, MS, a resident physician in the Department of Medicine, and Ashwin Kishtagari, MD, assistant professor of Medicine in the Division of Hematology and Oncology, the study required large numbers. 

The researchers pulled genetic sequencing data from three major population-level cohorts: the National Institutes of Health (NIH) All of Us Research Program, the UK (United Kingdom) Biobank and VUMC’s biobank, BioVU. 

With roughly 350,000 DNA samples collected to date, BioVU is the world’s largest repository of genetic material linked to de-identified electronic health records (EHRs) based at a single academic center.  

Access to whole genome sequences linked to EHRs for more than 107,000 adults enrolled in BioVU between 2006 and 2023 was provided through the Alliance for Genomic Discovery (AGD), a unique endeavor to accelerate the application of large-scale genomics to biomedical science and therapeutic development. 

Launched in 2022 by Nashville Biosciences LLC, a wholly owned VUMC subsidiary, and the global DNA sequencing giant Illumina Inc., AGD now includes eight major pharmaceutical companies that support the development and availability of whole genome sequences for research aimed at identifying disease associations and targets for intervention. 

The report in eClinicalMedicine “is one of the first papers to leverage data from the BioVU/Alliance for Genomic Discovery whole genome sequencing effort,” Bick said. “It also highlights how at VUMC medical trainees are doing cutting-edge research while developing as physicians.” 

Between the three biobanks, the researchers had access to 805,000 whole genome sequences. From this pool, they identified 8,114 individuals with CHIP who did not develop cytopenia and 1,260 who did. These 9,374 cases were matched with 24,749 controls who did not have CHIP. 

The annual blood cancer progression rate for participants with CHIP who did not develop cytopenia was nearly the same as the rate observed in the control population without CHIP (0.06% versus 0.04%), whereas the rate was 10 times higher for those with both CHIP and cytopenia (0.5% per year). 

Approximately 13% of participants with CHIP developed a cytopenia within five years. Men, smokers and older individuals (over 64) were at a higher risk of developing cytopenia, as were those who had two or more mutations or any high-risk mutations associated with CHIP. 

“Given the substantial risk of cytopenia, patients with multiple high-risk features may benefit from regular monitoring for cytopenia progression,” the researchers concluded. The good news is that this five-year window before the development of cytopenia and blood cancer “provides an opportunity for early intervention with potential disease-modifying therapies,” they wrote.  

Treatments for cytopenia range from drugs that stimulate the production of certain blood cell types to bone marrow or stem cell transplants. 

Co-authors from the Bick lab included rheumatology fellow Robert Corty, MD, PhD, Yash Pershad, an MD-PhD student, and Brian Sharber, MS. Other VUMC co-authors included faculty members Brett Heimlich, MD, PhD, Leo Luo, MD, Brent Ferrell Jr., MD, Michael Savona, MD, and Yaomin Xu, PhD. 

This research was supported by NIH grants DP5OD029586, R01AG088657, R01AG083736, and P30CA068485, the Burroughs Wellcome Fund Career Award for Medical Scientists, the Edward P. Evans Foundation, and the Pew Charitable Trusts and the Alexander and Margaret Stewart Trust. 

Savona holds the Beverly and George Rawlings Directorship. Bick is supported in part by a Hevolution/AFAR New Investigator Award in Aging Biology and Geroscience Research, and Brogan is supported in part by an American Society of Hematology HONORS Award.

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