Identification of clonal hematopoiesis mutations in solid tumor patients undergoing unpaired next-generation sequencing assays

Purpose: In this era of precision-based medicine, for optimal patient care, results reported from commercial next-generation sequencing assays should adequately reflect the burden of somatic mutations in the tumor being sequenced. Here, we sought to determine the prevalence of clonal hematopoiesis leading to possible misattribution of tumor mutation calls on unpaired FoundationMedicine® next-generation sequencing assays. Experimental Design: This was a retrospective cohort study of individuals undergoing next-generation sequencing of solid tumors from two large cancer centers. We identified and quantified mutations in genes known to be frequently altered in clonal hematopoiesis (DNMT3A, TET2, ASXL1, TP53, ATM, CHEK2, SF3B1, CBL, JAK2) that were returned to physicians on clinical FoundationMedicine® reports. For a subset of patients, we explored the frequency of true clonal hematopoiesis by comparing mutations on FoundationMedicine® reports with matched blood sequencing. Results: Mutations in genes that are frequently altered in clonal hematopoiesis were identified in 65% (1139/1757) of patients undergoing next-generation sequencing. When excluding TP53, which is often mutated in solid tumors, these events were still seen in 35% (619/1757) of patients. Utilizing paired blood specimens, we were able to confirm that 8% (18/226) of mutations reported in these genes were true clonal hematopoiesis events. The majority of DNMT3A mutations (64%, 7/11) and minority of TP53 mutations (4%, 2/50) were clonal hematopoiesis. Conclusion: Clonal hematopoiesis mutations are commonly reported on unpaired next-generation sequencing testing. It is important to recognize clonal hematopoiesis as a possible cause of misattribution of mutation origin when applying next-generation sequencing findings to a patient's care.

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