Genomic landscape of liquid biopsy mutations in TP53 and DNA damage genes in cancer patients
Damien Vasseur, Ahmadreza Arbab, Fabiola Giudici, Christophe Marzac, Stefan Michiels, Marco Tagliamento, Arnaud Bayle, Cristina Smolenschi, Madona Sakkal, Mihaela Aldea, Hela Sassi, Filippo Gustavo Dall’Olio, Noémie Pata-Merci, Sophie Cotteret, Alice Fiévet, Nathalie Auger, Luc Friboulet, Francesco Facchinetti, Arthur Géraud, Santiago Ponce, Antoine Hollebecque, Benjamin Besse, Jean Baptiste Micol, Antoîne Italiano, Ludovic Lacroix, Etienne Rouleau
Abstract
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 leads to the identification of mutations not confirmed in tissue. It becomes essential to describe the characteristics and consequences of these liquid biopsy-only mutations. In the STING protocol (Gustave Roussy, NCT04932525), 542 patients with advanced solid cancer had cfDNA-based and tissue-based NGS analysis (performed by FoundationOne® Liquid CDx and FoundationOne CDx™, respectively). Mutations identified in the liquid biopsy but not in the paired tissue were considered as liquid biopsy-only mutations irrespective of their variant allelic frequency (VAF). Out of 542 patients, 281 (51.8%) harbored at least one liquid biopsy-only mutation. These patients were significantly older, and more heavily pretreated. Liquid biopsy-only mutations occurring in TP53, and in DDR genes (ATM, CHEK2, ATR, BRCA2, and BRCA1) accounted for 90.8% of all the mutations. The median VAF of these mutations was generally low (0.37% and 0.40% for TP53 and DDR genes respectively). The variant type repartition depended on the gene. Liquid biopsy-only mutations affected hotspot in TP53 codon 273, 125, 195, 176, 237 or 280 and ATM codon 2891 and 3008. In a subset of 37 patients, 75.0%, 53.5% and 83.3% of the liquid biopsy-only mutations occurring respectively in ATM, TP53, and CHEK2 were confirmed in the matching whole blood sample. Although liquid biopsy-only mutations makes the interpretation of liquid biopsy results more complex, they have distinct characteristics making them more easily identifiable.