Deeper Understanding of Clonal Hematopoiesis Could Improve Cardiovascular Outcomes for Patients With Kidney Cancer

Maxine Sun, PhD, MPH

Additional research exploring the association between clonal hematopoiesis and cardiovascular health could help improve outcomes for patients with kidney cancer and identify those at higher risk for experiencing cardiac events, according to Maxine Sun, PhD, MPH.¹

"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 a presentation at the 2023 International Kidney Cancer Symposium. “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.”

Sun is a research scientist in the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts.

Clonal hematopoiesis is defined as the overrepresentation of blood cells derived from a single clone, which can also occur in individuals without cancer.² Additionally, TET2 mutations arecommon in the blood cells of individuals exhibiting clonal hematopoiesis and are associated with an increased risk of experiencing heart failure.³ Furthermore, TET2 deficiency in macrophages could promote inflammation through the pro-inflammatory cytokine interleukin 1β.⁴

“As people age, their tissues accumulate an increasing number of somatic mutations, 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 with clonal hematopoiesis in the general population (HR, 1.40; 95% CI, 1.1-1.8) as well an increased risk of incident coronary heart disease (HR, 2.0; 95% CI, 1.2-3.4) and ischemic stroke (HR, 2.6; 95% CI, 1.4-4.8).⁵

"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 (mCAs). 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, and autosomal mCAs 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 mCAs had an increased risk of death due to cardiovascular disease causes (HR, 2.03; 95% CI, 1.11-3.72; P = .022) and coronary artery disease causes (HR, 3.57; 95% CI, 1.44-8.84; P = .006).⁶

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.

References

1. Sun M. The effect of clonal hematopoiesis on cardiovascular outcomes in patients diagnosed with kidney cancer. Presented at: 2023 International Kidney Cancer Symposium; November 9-11, 2023; Nashville, TN.
2. Jaiswal S, Ebert BL. Clonal hematopoiesis in human aging and disease. Science. 2019;366(6465):eaan4673. doi:10.1126/science.aan4673
3. Sano S, Oshima K, Wang Y, et al. Tet2-mediated clonal hematopoiesis accelerates heart failure through a mechanism involving the IL-1β/NLRP3 Iiflammasome. J Am Coll Cardiol. 2018;71(8):875-886. doi:10.1016/j.jacc.2017.12.037
4. Fuster JJ, MacLauchlan S, Zuriaga MA, et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science. 2017;355(6327):842-847. doi:10.1126/science.aag1381
5. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488-98. doi:10.1056/NEJMoa1408617
6. Sun M, Cyr MC, Sandoval J, et al. Somatic Mosaic Chromosomal Alterations and Death of Cardiovascular Disease Causes among Cancer Survivors. Cancer Epidemiol Biomarkers Prev. 2023;32(6):776-783. doi:10.1158/1055-9965.EPI-22-1290