Genomic profiling of chemotherapy-related clonal hematopoiesis in patients with high-grade serous ovarian cancer

Abstract Background: Clonal hematopoiesis (CH) is identified as the presence of clonal populations of hematopoietic stem cells (HSC). 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 mutation(s) in HSCs, in the absence of hematological abnormalities. Previous studies have been 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; moreover, while previous CHIP studies are largely knowledge based and are limited to known hematologic genes or target gene panels, our study discovers novel CHIP mutations. Methods: Comprehensive ultra-high-depth whole exome sequencing using unique molecular barcode technologies was performed using plasma-derived cell-free DNA and matched white blood cells DNA and tumor DNA from pre-NACT (n=12) and post-NACT (n=12) samples of patients with HGSC who have excellent or poor response to NACT. Using spike-in mutated DNAs as positive controls, we detected variant alleles at 1% variant allele frequency. Results: We identified on average about 3,000 candidate CHIP variants in one patient. Among these, 1,977 variants affecting 1,375 genes were recurrently found in more than one patient. These CHIP genes include not only previous reported CHIP genes (e.g. DNMT3A, JAK2, TET2, and KMT2D) but also many novel CHIP candidates (such as RPTN, MTCH2, FAM186A, CACNA1A, FCGBP, and MUC3A). A number of CHIP mutations were uniquely found enriched in post-chemotherapy samples (e.g. ARID1A T290P, TP53 G245D, SMARCA4 G495D, and CIC T2456P). Interestingly, there is a strong enrichment of COSMIC cancer census genes in CHIP genes identified in every patient. Conclusions: Our findings corroborate the notion that CHIP mutations are present in nonmalignant blood cells of patients with HGSC, and some are enriched after chemotherapy. Moreover, our innovative sequencing approach allowed discovery of novel candidate CHIP genes. The systematic identification of CHIP in patients with HGSC might be an important new clinical consideration when establishing chemotherapy protocols. Citation Format: Sara Corvigno, Jun Yao, Li Zhao, Amma Asare, Joseph Celestino, Richard Hajek, Ency Arboleda Goette, Elaine Stur, Emine Bayraktar, Mark S Kim, Ping Song, Qingxiu Zhang, Xingzhi Song, Mohammad Mohammad, Kenna Shaw, Jianhua Zhang, Karen Lu, Amir Jazaeri, Shannon Westin, Anil Sood, Sanghoon Lee. Genomic profiling of chemotherapy-related clonal hematopoiesis in patients with high-grade serous ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5473.