Tatiana Mögele, Kathrin Hildebrand, Aziz Sultan, Sebastian Sommer, Lukas Rentschler, Maria Kling, Irmengard Sax, Matthias Schlesner, Bruno Märkl, Martin Trepel, Maximilian Schmutz, Rainer Claus
- Tumor heterogeneity encompasses genetic, epigenetic, and phenotypic diversity, impacting treatment response and resistance. Spatial heterogeneity occurs both inter- and intra-lesionally, while temporal heterogeneity results from clonal evolution. High-throughput technologies like next-generation sequencing (NGS) enhance tumor characterization, but conventional biopsies still do not adequately capture genetic heterogeneity. Liquid biopsy (LBx), analyzing circulating tumor DNA (ctDNA), provides a minimally invasive alternative, offering real-time tumor evolution insights and identifying resistance mutations overlooked by tissue biopsies. This study evaluates the capability of LBx to capture tumor heterogeneity by comparing genetic profiles from multiple metastatic lesions and LBx samples. Eight patients from the Augsburger Longitudinal Plasma Study with various types of cancer provided 56 postmortem tissue samples, which were compared against pre-mortem LBx-derived circulating-free DNATumor heterogeneity encompasses genetic, epigenetic, and phenotypic diversity, impacting treatment response and resistance. Spatial heterogeneity occurs both inter- and intra-lesionally, while temporal heterogeneity results from clonal evolution. High-throughput technologies like next-generation sequencing (NGS) enhance tumor characterization, but conventional biopsies still do not adequately capture genetic heterogeneity. Liquid biopsy (LBx), analyzing circulating tumor DNA (ctDNA), provides a minimally invasive alternative, offering real-time tumor evolution insights and identifying resistance mutations overlooked by tissue biopsies. This study evaluates the capability of LBx to capture tumor heterogeneity by comparing genetic profiles from multiple metastatic lesions and LBx samples. Eight patients from the Augsburger Longitudinal Plasma Study with various types of cancer provided 56 postmortem tissue samples, which were compared against pre-mortem LBx-derived circulating-free DNA sequenced by NGS. Tissue analyses revealed significant mutational diversity (4-12 mutations per patient, VAFs: 1.5-71.4%), with distinct intra- and inter-lesional heterogeneity. LBx identified 51 variants (4-17 per patient, VAFs: 0.2-31.1%), which overlapped with mutations from the tissue samples by 33-92%. Notably, 22 tissue variants were absent in LBx, whereas 18 LBx-exclusive variants were detected (VAFs: 0.2-2.8%). LBx effectively captures tumor heterogeneity, but should be used in conjunction with tissue biopsies for comprehensive genetic profiling.…
