Genetic Mutations May Explain Heart Events in Some Patients With Kidney Cancer

Some patients with kidney cancer may have an increased risk for heart-related events such as heart attacks and strokes, and more research into the link between clonal hematopoiesis and heart health may improve outcomes for these patients, an expert discussed.

Maxine Sun, a research scientist in the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, presented on this topic at the 2023 International Kidney Cancer Symposium.

"Cardiovascular health is becoming increasingly important for patients diagnosed with kidney cancer as we are increasing the number of therapies that are available in the first line and subsequent lines,” Sun said during the presentation. “Clonal hematopoiesis appears to have an influence on the risk of cardiovascular outcomes in patients diagnosed with kidney cancers. Therefore, there is a definite interest in trying to (further) investigate (its) role and to try to understand and characterize the specific biological pathways (of) this potential association.”

Clonal hematopoiesis refers to when a patient has too many blood cells that originate from one group, which can happen even if a person doesn't have cancer. People with clonal hematopoiesis often have TET2 mutations in their blood cells, and this can raise the chances of getting heart failure. Moreover, if there is not enough TET2 in certain immune cells called macrophages, it might make the body more prone to inflammation by increasing the levels of a molecule called interleukin 1β, which causes inflammation.

“As people age, their tissues accumulate an increasing number of somatic mutations (an alteration in DNA that occurs after conception), most of which are inconsequential. Occasionally, there will be a mutation that will arise and will confer this fitness advantage on a cell,” Sun said. “When this process happens in the hematopoietic system, a large proportion of circulating blood cells end up derived from this single mutated stem cell, and this particular outgrowth is what is termed as clonal hematopoiesis.”

Clonal hematopoiesis is a known biomarker in hematologic cancer for its development and progression, Sun noted. Additionally, findings from a 2014 study showed an increase in all-cause mortality (death from any cause) with clonal hematopoiesis in the general population as well an increased risk of incident coronary heart disease (narrowing or blockage of the coronary arteries) and ischemic stroke (when a blood clot blocks an artery that leads to the brain).

"What was surprising and unexpected about that study was that when they dug a little bit deeper, they found that the cause of death driving that increased risk of all-cause mortality wasn't actually caused by somatological cancer; it was mostly driven by incident coronary heart disease, as well as ischemic stroke,” Sun said.

Sun also delved into mosaic chromosomal alterations, which refers to changes or abnormalities in a person’s chromosomes that are not the same in all cells of the body. She noted the mosaic loss of chromosome Y has been associated with an increase in all-cause mortality, Alzheimer’s, autoimmune disease, diabetes, cancer and cardiovascular events.

In addition, autosomal (or related to the 22 pairs of numbered chromosomes found in most human cells) mosaic chromosomal alterations have been linked with an increase in hematologic cancers and all-cause mortality.

Specifically for patients with renal cell carcinoma, findings from a 2023 study published in Cancer Epidemiology, Biomarkers & Prevention by Sun and colleagues showed that those harboring mosaic chromosomal alterations had an increased risk of death due to cardiovascular disease causes and coronary artery disease causes.

Based on the current literature and data surrounding the association between clonal hematopoiesis and cardiovascular health, Sun said future research is being designed to better understand this correlation and identify patients with kidney cancer who may be at higher risk for worse cardiovascular outcomes.

"We're going to propose looking at associations of clonal hematopoiesis, whether it be clonal hematopoiesis of indeterminate potential (CHIP) or (other biomarkers), on cardiovascular outcomes in patients diagnosed with kidney cancer using institutional data, such as a Dana-Farber Cancer Institute cohort, and likely a bigger population–based cohort with genomic data. If we're able to replicate the effect across these different cohorts, it (would) strengthen the robustness of this marker,” Sun concluded.

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