Genomic landscape characterization and comparative analysis of tissue and liquid-based next-generation sequencing in anaplastic thyroid carcinoma in Taiwan

Anaplastic thyroid carcinoma (ATC) is an aggressive disease that requires prompt diagnosis and multimodal treatment. Recent advancements in targeted therapies have offered new treatment options for patients with ATC, potentially improving their clinical outcomes. Ongoing progress in high-throughput next-generation sequencing (NGS) has enabled clinicians to comprehensively characterize the genomic landscape of tumors, guide treatment decisions, and facilitate clinical trial enrollment. The role of liquid NGS in ATC remains unclear, particularly in cases where tissue NGS is not feasible or yields inadequate results. This study assessed patients with ATC treated at Chang Gung Memorial Hospital, Linkou, between 2011 and 2023. Among these, 26 patients had adequate tissue for commercially available tissue NGS (ACTOnco®+, 440 genes), 15 had access to a commercially available liquid NGS platform (ACTMonitor®+, 50 genes), and 13 patients underwent both tissue and liquid NGS. The genetic alterations observed in ATC exhibited a high degree of heterogeneity, involving several pathways, including RAS/RAF/MEK/ERK (73.1%), PI3K/AKT/mTOR (57.7%), cell cycle regulation (92.3%), other receptor tyrosine kinases (65.4%), DNA damage response (50.0%), DNA mismatch repair (MMR, 34.6%, including MLH1, MSH6, MSH2, and PMS1), and chromatin remodeling (76.9%). The most frequently mutated genes in tissue NGS were TP53 (17/26, 65.4%) and BRAF (8/26, 30.8%). Among the 13 pairs analyzed on both platforms, the concordance rates were 84.6% and 69.2% for BRAF and TP53, respectively. Among two patients without sufficient tissue for NGS, liquid NGS provided additional information on genetic alterations. Two ATC patients treated with dabrafenib and trametinib had treatment-naïve and post-treatment tissue samples for NGS, but only one patient (two samples; ATC01 after) showed copy number gain over genes, which may be associated with resistance. NGS platforms, whether applied to tissue or liquid samples, can empower clinicians to identify targetable oncogenic events in ATC. Liquid biopsy provides supplementary information when the tissue is insufficient for NGS. Additional studies are needed to understand the resistance mechanisms associated with BRAF-targeted therapy and explore strategies to overcome resistance.