High Prevalence of TBC1D12 5'UTR Mutations in Anaplastic Thyroid Cancer

Background: Anaplastic thyroid cancer (ATC) is a rare but one of the most lethal types of human cancer. Although increasing evidence demonstrated that ATC tumors had a high mutation burden, little is known about the aberrancy of the noncoding genome of ATC except the well-investigated telomerase reverse transcriptase (TERT) promoter mutations. Methods: The mutational statuses of TBC1D12 5' untranslated region (5'UTR), GPR126 intron 6, SDHD and PLEKHS1 promoters, as well as the TERT promoter and BRAF^V600E mutations were determined using Sanger sequencing in 28 patients with ATC (19 women and 9 men) with a median (interquartile range) age of 64 (55-71) years, 14 thyroid cancer cell lines and a normal thyroid cell line. The prevalence of TBC1D12 5'UTR mutations in papillary thyroid cancer (PTC) and their association with clinicopathologic characteristics were explored by analyzing The Cancer Genome Atlas thyroid cancer dataset. Results: The noncoding mutations in TERT, SDHD and PLEKHS1 promoters, TBC1D12 5'UTR, and GPR126 intron 6 were collectively found in 82.1% (23/28) of ATC samples. Specifically, TERT promoter mutations were detected in 22 (78.6%) samples; GPR126 intron mutations were detected in 2 (7.1%) samples; and both SDHD and PLEKHS1 promoter mutations were detected in 1 (3.6%) ATC sample. Two hotspot mutations in TBC1D12 5'UTR were observed in 14 of 28 (50%) ATCs, 7 of 492 (1.4%) PTCs, and 1 cell line derived from ATC. TBC1D12 5'UTR mutations were significantly associated with older age at diagnosis (60 vs. 46 for wild type, p = 0.003), pathological T3/T4 stage (85.7% vs. 37.7%, p = 0.010), and advanced tumor stages (85.7% vs. 32.5%, p = 0.006) in PTC. Conclusions: This preliminary study for the first time showed a high prevalence of TBC1D12 5'UTR mutations in ATC and indicated an association between TBC1D12 mutation and aggressive characteristics of PTC, which needs to be confirmed in large cohort studies.