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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