Comprehensive next-generation profiling of clonal hematopoiesis in cancer patients using paired tumor-blood sequencing for guiding personalized therapies.

Abstract

e13662 Background: Clonal hematopoiesis (CH) is commonly observed during genomic profiling of cancer patients. However, the relevance of CH in Chinese patients has yet to be characterized. Methods: We analyzed next-generation sequencing (NGS) data from blood and matched solid tumors of 4,544 cancer patients. For delineating the impact of CH on panel-based estimation of tumor mutational burden (TMB), its correlation with whole-exome-based TMB calculation was analyzed in an independent cohort of 175 patients. Results: A total of 1,749 CH mutations in 237 genes were identified in the blood of 1,301 (28.6%) patients, among which 26% carried more than one CH mutations. DMNT3A (35.8%), TET2 (13.2%), NOTCH1 (4.8%), ASXL1 (3.8%) and TP53 (3.7%) were among the top altered CH genes, while the prevalence of several other known CH genes, including JAK2 and SF3B1, were below 1%. The predominant hot-spot mutation in DNMT3A at R882 showed varying frequencies of different amino acid changes. An age-associated accumulation of CH events was observed, with alterations in DNMT3A, TET2, ASXL1 and TP53 showing evidence of early changes. A large proportion (74.1%, 1296 mutations) of CH was detectable in the matched tumors. Of these, 453 (25.9%) were functionally annotated as oncogenic or likely oncogenic, including two EGFR kinase domain mutations (V742I and R776H), one KRAS mutation (F156L) and a loss-of-function BRCA2 mutation. With respect to immunotherapy, while CH was not associated with microsatellite instability, it had a negative impact on accurate TMB determination. Consequently, we developed a novel panel-based TMB estimation algorithm with CH filters that showed optimal concordance with exome sequencing in an independent cohort of 175 patients. Conclusions: Our findings highlight the clinical significance of CH in fulfilling the promise of precision medicine and emphasize the need for matched tumor-blood sequencing.