Next-generation sequencing (NGS) assays based on plasma cell-free DNA (cfDNA), are increasingly used for clinical trials inclusion. Their optimized limit of detection applied to a large number of genes complicates the distinction between clonal hematopoiesis-related (CH-related) and solid tumor-related (ST-related) mutations. It becomes essential to describe the characteristics and consequences of these CH-related mutations.
In the STING protocol (Gustave Roussy, NCT04932525), 519 patients with an advanced solid cancer had cfDNA-based and tissue-based NGS analysis (FoundationOne Liquid CDx and FoundationOne CDx, respectively). Concordant mutations between tissue and liquid were considered as ST-related mutations. Mutations identified in the liquid biopsy but not in the paired tissue were considered as unconfirmed. Finally the subgroup of unconfirmed mutations occurring in ASXL1, ATM, CHEK2, DNMT3A, TET2 and TP53 were defined as CH-related mutations irrespective of their variant allelic frequencies (VAF).
Among the 519 patients, 371 (71.5%) harbored at least one unconfirmed mutation and 288 (55.5%) at least one CH-related mutation. A total of 557 mutations were CH-related: 75% were identified with VAF lower than 1.5%. Frameshift mutations were more frequent in CH-related mutations (p<0.001). We report new CH-related hotspot positions in TP53 codons 131, 195 and 280 and in ATM codon 2891. In a subset of 30 patients with both whole blood and plasma available, 42 of the 54 unconfirmed mutations (77.8%) were present in the whole blood, with 100% of the mutations occurring in ATM (n=12). Patients with at least one CH-related mutation were significantly older (p<0.001). Of the 294 patients with a CRP dosage, the 164 presenting with an increased CRP had an average of 2.8 CH-related mutations compared to 1.8 for the patients with normal CRP value (p=0.015).
CH-related mutations have distinct characteristics from ST-related mutations, making them more easily identifiable.
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