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Abstract Background: Hematopoietic lineage differentiation is subjected to genetic mutations that, due to fitness advantages, might give rise to clonally expanded populations. Clonal hematopoiesis of indeterminate potential (CHIP) is defined as the outgrowth of a single clone driven by acquired somatic mutations in hematopoietic stem cells (HSCs), in the absence of hematological abnormalities. Previous studies have shown the association of CH with aging and a higher risk of developing secondary hematologic malignancies in cancer patients treated with chemotherapy agents. It is therefore of great interest to study CH incidence prior to and post chemotherapy exposure and its association with the evolution of hematologic malignancies. We aimed to characterize CHIP variants of a highly selected group of patients with high-grade serous ovarian cancer (HGSC) who underwent neoadjuvant chemotherapy (NACT). Methods: Comprehensive ultra-high-depth whole exome sequencing, employing unique molecular barcode technologies, was performed using plasma-derived cell-free DNA (cfDNA) and matched white blood cells (WBC) DNA and tumor DNA from pre-NACT (n=10) and post-NACT (n=10) samples of patients with HGSC. CHIP variants were defined as heterozygous variants found in both the WBC and cfDNA samples from the same patients with variant allele frequency less than 5% in the WBC and higher than 0. 5% in cfDNA samples. Results: Our analysis identified 93, 088 variants, impacting 13, 780 genes. Among them, 463 variants were already known and published, and 5, 548 variants were common to the COSMIC genes signature. The number of CHIP variants significantly decreased after chemotherapy (p = 0. 004). We then focused on CHIP variants enriched after chemotherapy and identified 77 that showed higher VAF in post-NACT cfDNA samples, which may be associated with the development of therapy-related acute myeloid leukemia/myelodysplastic syndrome (t-AML/MDS). Among them, interestingly, we found a missense mutation with protein change in CDK12 (chr17₃9492765GT). We noticed that 38% of the CHIP variants found in cfDNA samples, were also found in matched tumor samples. Among these, another CDK12 missense mutation (chr17₃9492768AT) showed higher VAF in post-NACT tumors. Conclusions: Our innovative approach detected a higher number of CHIP variants than currently characterized. Analysis of cfDNA from HGSC patients consistently demonstrated a reduction in CHIP mutations post-NACT. The subset of variants with increased VAF post-NACT may be associated with therapy-related t-AML/MDS. The detection of cfDNA CHIP variants in matched tumors highlights the potential predictive role of CHIP in t-AML/MDS development, emphasizing its consideration in therapeutic protocols. Citation Format: Sara Corvigno, Amma Asare, Jun Yao, Li Zhao, Nicole Fleming, Joseph Celestino, Richard A. Hajek, Ency A. Arboleda Goette, Ridge T. Rogers, Tri V. Nguyen, Raymond N. Montoya, Karen H. Lu, Amir A. Jazaeri, Shannon N. Westin, Anil K. Sood, Sanghoon Lee. Identification of novel chemotherapy-related CHIP variations in patients with high-grade serous ovarian cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6407.
Corvigno et al. (Fri,) studied this question.