Comprehensive genomic profiling from C‐CAT database unveiled over 80% presence of oncogenic drivers in anaplastic thyroid carcinoma including BRAF, RAS family, NF1, and FGFR1

Abstract Objective Anaplastic thyroid carcinoma (ATC) is considered a very aggressive carcinoma and has been difficult to treat with therapeutic strategies. This study examines the landscape of genomic alteration in ATC, including the BRAF V600E mutation, and its clinical implications. Design, Patients and Mesurement A retrospective observational study was conducted using collected at the Center for Cancer Genomics and Advanced Therapeutics (C‐CAT) in Japan, utilizing comprehensive genomic profiling data from 102 ATC cases. Additionally, AACR‐GENIE data from 267 cases were analysed for validation. Statistical methods, including the conditional Kendall tau statistic and χ 2 tests, were employed for survival analysis and gene mutation comparisons. Results Among 102 ATCs, BRAF , RAS , and other driver mutations were found in 83 cases (81.2%). The prevalence of BRAF V600E mutations was as high as 60%. Co‐mutation analysis identified different genomic profiles in the BRAF, RAS , and wild‐type groups. Despite the diverse molecular backgrounds, no significant differences in clinical variables and overall survival were observed. The analysis considering left‐side amputation suggested that RAS mutations had a poorer prognosis. In the BRAF/RAS wild‐type group, FGFR1 and NF1 were identified as driver mutations, with an accumulation of copy number variations and less TERT promoter mutations. This molecular subgrouping was also supported by the AACR‐GENIE data. Conclusions Comprehensive genomic analysis of ATC in Japan revealed distinct molecular subgroups, highlighting the importance of BRAF V600E mutations, particularly V600E, as potential therapeutic targets and suggest the relevance of tailor‐made therapeutic strategies based on genomic profiling.