Abstract 4916: Co-occurring clonal hematopoiesis in UK Biobank participants with prior cancer

Abstract Clonal hematopoiesis (CH) describes the age-related clonal expansion of hematopoietic stem cells, driven by either acquired mutations in driver genes (referred to as clonal hematopoiesis of indeterminate potential (CHIP)), or by large-scale mosaic chromosomal alterations (mCAs). Evidence from previous studies indicate anti-cancer agents, such as chemotherapy and radiation therapy, may promote the expansion of clones with DNA damage response mutations (e.g., TP53, PPM1D, and CHEK2). However, the co-occurrence of CHIP and mCAs in participants with prior cancer has not been extensively characterized. We therefore examined the frequency of co-occurring CHIP and mCAs to further evaluate the landscape of CH within individuals with prior cancer diagnoses. We analyzed sequencing and genotyping array data from 34, 339 UK Biobank participants with a prior cancer diagnosis. Among these, 2, 756 CHIP events were detected in 2, 470 (7.2%) of participants, at a frequency 1.5 times greater than those participants with no prior cancer diagnosis (N = 453, 807). TP53, PPM1D, MYD88, ATM, JAK2, and CALR CHIP mutations in particular were detected at increased rates in those with prior cancer (ORs ranging from 1.9 for TP53 mutations to 6.1 for CALR mutations, p < 6.5 × 10-4). Autosomal mCAs were also detected at a higher rate compared to those with no prior cancer diagnoses; 2, 100 events were detected in 1, 665 participants (4.8% vs 3.0% in cancer-free participants). Specifically, mCAs on 10 chromosomes (chr22, chr11, chr12, chr17, chr1, chr19, chr20, chr9, chr7, chr13, respectively) were more frequent (OR = 1.3 - 2.6, p < 6.4 × 10-3). Co-occurring CH was characterized in three groups: CHIP-CHIP, mCA-mCA, CHIP-mCA. Among CHIP-CHIP events, 4 enriched co-occurrences (p < 2.7 × 10-5) were observed, all of which included TET2 or SRSF2 mutations. For mCA-mCA events, enrichment was observed for whole chromosome gains of chr3, chr12, and chr18. Approximately 1% of participants had both detectable CHIP and mCA events. A total of 12 specific CHIP-mCA co-occurrences were enriched; 3 of which were overlapping and also identified in the population with no prior cancer diagnosis (e.g., TP53 CHIP and chr17p loss) and 4 of which were not observed in cancer-free individuals. DNMT3A-mLOY CH was observed less frequently than expected in prior cancer cases. These observations suggest potential instances of both mutual exclusivity and cooperation among CH types in participants with prior cancer diagnoses. The increased detection rate of some co-occurrences in this population, compared to those with no prior cancer, may reflect selective pressures of cancer treatment. Citation Format: Kara Marie Barnao, Aubrey K. Hubbard, Irenaeus Chan, Weiyin Zhou, Corey D. Young, Rebecca L. Kelly, Derek W. Brown, Giulio Genovese, Duc Tran, Yin Cao, Stephen J. Chanock, Kelly L. Bolton, Mitchell J. Machiela. Co-occurring clonal hematopoiesis in UK Biobank participants with prior cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4916.