Impact of clonal hematopoiesis mutations on toxicity and outcomes following oncologic therapy

PROJECT SUMMARY Studies in healthy individuals have shown that acquired DNA mutations are surprisingly common in normal- appearing tissues. Clonal hematopoiesis (CH) mutations are acquired mutations in the blood present in the majority of older individuals.

CH mutations are also frequent among individuals with solid malignancy; are associated with past receipt of oncologic therapy, in particular radiation therapy; and are associated with worse overall survival.

This project will address key knowledge gaps by investigating whether CH mutations are associated with adverse oncologic treatment toxicity and outcomes in patients with solid malignancy (Aim 1), how oncologic therapy impacts the frequency and characteristics of CH mutations in patients with solid malignancy (Aim 2), and whether there are actionable intermediary biomarkers of adverse outcomes among individuals with CH mutations (Aim 3).

We will address these aims by undertaking targeted DNA sequencing using existing biospecimens from prospective cohorts of patients undergoing oncologic therapy for solid malignancy (Aims 1 and 2) and using existing clinical and genetic data from a large prospective biobank (Aim 3). Our approach leverages unique patient resources and novel methodology.

Completion of these aims will provide key insight regarding the importance of CH mutations in patients with solid malignancy and guide future investigations to determine whether knowledge of CH mutations can improve cancer care. The applicant, Dr. Kevin T. Nead, MD, MPhil, is an assistant professor in epidemiology and radiation oncology at MD Anderson Cancer Center.

This study is in line with Dr.

Nead?s long-term career goal to become an independent, R01 funded investigator studying the use of inherited and acquired patient-level genetic data to improve cancer prevention and treatment paradigms. The overall career development objectives of Dr.

Nead?s proposal are to 1) expand his knowledge and expertise in genetics/genomics, bioinformatics, somatic mutation analysis, and study design; 2) complete an interdisciplinary research plan and establish a published body of work on acquired mutations in normal tissues and oncology care; and 3) build a platform for his successful transition to an independent investigator.

During the award period Dr. Nead will devote at least 75% of his effort to the proposed project and career development activities. Dr.

Paul Scheet, the candidate?s primary mentor, is chair of the Department of Epidemiology, an international expert in the study of acquired mutations in normal tissue, and has received multiple awards for the quality of his mentorship and teaching. Dr.

Nead will also benefit from the rich training environment and outstanding resources and mentorship available at MD Anderson Cancer Center for the proposed project. Completion of the proposed research and career development plan will give Dr.

Nead the necessary knowledge and skills to transition to independence and to pursue an impactful career improving cancer prevention and care.