Abstract 1511: Longitudinal whole genome sequencing to investigate clonal hematopoiesis dynamics

Abstract Clonal hematopoiesis (CH) is the presence of clonal populations of hematopoietic stem cells, which arise when a cell acquires a somatic mutation and then undergoes clonal expansion. The presence of CH is strongly associated with age. Clonal hematopoiesis of indeterminate potential (CHIP) mutations is defined by having a mutation in a gene commonly altered in blood cancers. CHIP is associated with increased risk of illnesses such as blood cancer and cardiovascular diseases. In addition to CHIP mutations, other somatic mutations can drive CH. To comprehensively characterize CH dynamics, we conducted whole genome sequencing (WGS) of blood samples from a community-based brain aging cohort, sequencing multiple samples that were collected across multiple time points. The University of Kentucky (UK) Alzheimer's Disease Research Center clinical cohort comprises a continuously replenished group of approximately 800 participants followed longitudinally. We selected 12 participants for a pilot study using the following criteria: each individual had 3 blood draws, and a minimum of 2 years between draws. WGS for these samples was performed at the Genomics Core Laboratory at UK. For all participants the age at first blood draw ≤ 89 years (median age: 80.5, range: 66-89), age at last blood draw ≤ 95 (median age: 87, range: 80 - 95). The time in years between first and last blood draw ranged from 6 to 12 years. 75% of participants were female and 25% were male. The mean average coverage was 54.4X. Alignment and variant calling were performed using the Illumina DRAGEN Somatic pipeline. Post pipeline filtering steps include filtering out variants in low complexity and blacklisted regions and removal of putative germline variants. Using stringent quality control metrics, 3/12 (25%) individuals had CHIP in one of the 74 canonical CHIP genes. Of these participants, 2 had DNMT3A CHIP. One participant had DNMT3A CHIP at age 87 (last blood draw), but not at age 80 or 83. For the other participant with DNMT3A CHIP, the mutation was present in all 3 blood draws from age 68, 77, and 80 years and with mutant allele fraction (MAF) ranging between 10-16%. TET2 CHIP was detected in one participant at age 90 (MAF 10%) and 95 (MAF 15%), but not at age 84. Our observations support previous studies showing that CHIP is common in later life. This pilot study provides an opportunity to conduct more in-depth investigations of clonal dynamics in later life and expand these investigations to non-canonical CH driver mutations and mosaic chromosomal alterations. We are pursuing this opportunity and leveraging the longitudinal study design to develop novel approaches for distinguishing germline and somatic variants to improve methods for CHIP mutation calling. Citation Format: Rohini Chebbi, Steven Estus, Elif P. Coskun, David W. Fardo, Gregory A. Jicha, Peter T. Nelson, Erin L. Abner, Yasminka A. Jakubek, . Longitudinal whole genome sequencing to investigate clonal hematopoiesis dynamics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1511.