Impact of Cancer Therapy-Related Clonal Hematopoiesis on Cardiovascular Diseases

About This Grant

PROJECT SUMMARY Advances in cancer treatment have led to longer survival, making late cardiovascular complications a growing concern in survivorship care. One newly recognized contributor to heart disease in cancer patients is clonal hematopoiesis of indeterminate potential (CHIP), a clonal expansion of hematopoietic stem cells due to acquired somatic mutations. CHIP has been associated with elevated risks of cardiovascular diseases (CVD) and higher all-cause mortality, independent of traditional cardiovascular risk factors. While genotoxic cancer therapies such as radiotherapy and chemotherapy have been implicated in CHIP pathogenesis, the prevalence of therapy-related CHIP and its impact on cardiovascular outcomes remain severely understudied. Furthermore, there are currently no clinical guidelines for screening CHIP in cancer patients, nor validated tools to stratify CVD risk in individuals with CHIP. The proposed study will directly address these unmet needs by defining the relationship between cancer therapies and CHIP development, evaluating the impact of therapy-related CHIP on CVD outcomes, and developing a CVD risk stratification tool tailored for cancer survivors. The research proposal leverages our Vanderbilt BioVU DNA biobank which has recently completed whole genome sequencing of >250,000 patients, including >78,000 cancer patients. The proposal consists of three aims: 1) to identify the prevalence and risk factors for CHIP in cancer patients; 2) to define and predict the impact of CHIP on CVD risk; and 3) to track the longitudinal clonal dynamics of therapy-related CHIP. Successful completion of these aims will lay the groundwork for a precision survivorship model that integrates CHIP status into a comprehensive cardiovascular risk assessment, more personalized cancer treatment strategies, and future interventional trials designed to reduce long-term CVD risk in this growing patient population. Dr. Leo Luo is a radiation oncologist and physician-scientist at Vanderbilt University Medical Center (VUMC). His research and career development will be conducted at VUMC, which offers a rich and collaborative research environment, extensive sources for early-career investigators, and an outstanding track record of successful mentorship. In addition to his primary mentor, Dr. Luo has established a research advisory committee composed of internationally recognized experts in CHIP, cardiovascular research, and bioinformatics. His structured training plan in cardio-oncology, genomic analysis, and epidemiology will develop the skills necessary for him to pursue a research program that is distinct from that of his mentors and facilitate his transition to an independent, R01-funded physician-scientist.