Abstract
Disclosure: S. Kwak: None. E. Lee: None. Y. Park: None. Although most follicular thyroid cancers (FTCs) show excellent prognosis, more than 5% accompany distant metastasis, often diagnosed unexpectedly in the advanced stage. Genetic or genomic markers have been shown to be useful as a prognostic tool in many cancers, but it is unclear whether genetic markers predicting the metastatic potential of FTCs exist. To investigate, 11 pairs of matched formalin fixed paraffin embedded tissue samples of primary (PTM1) and metastatic tumors (MT) from FTC patients with distant metastasis were analyzed by whole exome sequencing. For validation, 78 unmatched FTC samples including 49 well-differentiated tumors, 15 poorly-differentiated tumors and 14 anaplastic thyroid cancer (ATC) samples were analyzed by targeted sequencing. Among the 11 paired PTM1 and MT tumors, 10 showed concordant driver mutations (NRAS, HRAS, DICER1, EIF1AX), and the TERT promoter mutation was concordantly found in 6 pairs. However, the concordance rate of other somatic mutations in paired samples were found to be only 16.2%. Other mutational characteristics such as mutational signatures and CNVs also differed, suggesting the independent subclonal evolution of the paired MT from the PTM1 after metastasis. Interestingly, the frequency of mutations including driver, TERT promoter, and other mutations was lower in primary tumors without metastases (PTM0). Mutational characteristics of PTM0 also differed from those of PTM1 and MT, suggesting that the mutational or molecular characteristics of PTs at the time of diagnosis may distinguish metastatic potential. In a pooled analysis including published data of follicular patterned tumors, we found that metastatic or aggressive tumors were more likely to have the RAS mutation, which tended to be coupled with TERT, DICER1, EIF1AX, and TP53, gradually from minimally invasive FTC, widely invasive FTC to poorly differentiated thyroid cancer (PDTC) and ATC. Transcriptomic profiles from The Cancer Genome Atlas (TCGA) and our data (SNUH) showed RAS(+)/TERT(+) mutated tumors and RAS(+)/TERT(-) tumors had differences in several intracellular signal pathways. Therefore, when follicular neoplasm is diagnosed, NRAS and HRAS mutation tests followed by TERT promoter mutation tests may help diagnose FTCs with metastatic potential. Other genetic mutations could be candidates for a diagnostic or prognostic marker, and large-scale validation studies are warranted.This study was funded by the Basic Science Research Program through the National Research Foundation of Korea, funded by the Ministry of Science, ICT & Future Planning (NRF-2019R1A2C2084332). Presentation: Thursday, June 15, 2023