Mutational profiling of poorly differentiated and anaplastic thyroid carcinoma by the use of targeted next‐generation sequencing

Abstract

Aims To characterise the mutational profiles of poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) and to identify markers with potential diagnostic, prognostic and therapeutic significance. Methods and results Targeted next‐generation sequencing with a panel of 18 thyroid carcinoma‐related genes was performed on tissue samples from 41 PDTC and 25 ATC patients. Genetic alterations and their correlations with clinicopathological factors, including survival outcomes, were also analysed. Our results showed that ATC had significantly higher mutation rates of BRAF, TP53, TERT and PIK3CA than PDTC (P = 0.005, P = 0.007, P = 0.005, and P = 0.033, respectively). Nine (69%) ATC cases with papillary thyroid carcinoma (PTC) components harboured BRAF mutations, all of which coexisted with a late mutation event (TP53, TERT, or PIK3CA). Nine cases with oncogenic fusion (six RET cases, one NTRK1 case, one ALK case, and one PPARG case) were identified in 41 PDTCs, whereas only one case with oncogenic fusion (NTRK1) was found among 25 ATCs. Moreover, all six cases of RET fusion were found in PDTC with PTC components, accounting for 33%. In PDTC/ATC patients, concurrent TERT and PIK3CA mutations were associated with poor overall survival after adjustment for TNM stage (P = 0.001). Conclusions ATC with PTC components is typically characterised by a BRAF mutation with a late mutation event, whereas PDTC with PTC components is more closely correlated with RET fusion. TERT and concurrent PIK3CA mutations predict worse overall survival in PDTC/ATC patients.

Risk Stratification Study of Indeterminate Thyroid Nodules with a next-generation Sequencing Assay with Residual ThinPrep® Material

“…In this way, we detected all single-nucleotide variants in these 18 genes and any gene fusions involving RET, NTRK1, ETV6, ALK, and PPARG. The design of 18-gene panel is based on data from public database and previous study in histology specimens [7,8]. bioanalyzer high-sensitivity DNA assay was performed to assess the quality and size of the fragments.…”

Characterization of Driver Mutations in Anaplastic Thyroid Carcinoma Identifies RAS and PIK3CA Mutations as Negative Survival Predictors

“…The BRAF-driven PTC has lower expression of thyroid differentiation genes, a higher risk of tumor recurrence, and strong MAP kinase signaling activation as opposed to activation of both MAP kinase and PI3 kinase pathways in RAS-driven PTC [7]. RAS and BRAF V600E mutations were also commonly mutated genes in ATC [8][9][10][11][12][13][14][15][16][17]. Studies indicated that RAS-driven and BRAF-driven ATC share homogenous transcriptome with an undifferentiated thyroid gene expression profile [9,18].…”

Histological features of BRAF V600E‐mutant anaplastic thyroid carcinoma

“…These results are consistent with those of Duan and colleagues, who reported a BRAF V600E mutation rate of 56% for their ATC cohort overall and 85% in their ATC with a PTC component. 5 We recognise that our cohort size is limited. Additionally, we only studied resected ATC.…”

“…This result is consistent with prior literature. [4][5][6][7][8][9][10][11][12][13] In the referenced studies, the overall BRAF V600E mutation rate is 30%, although the mutation rate varies widely between studies. This wide range may, in part, reflect differences in cohort characteristics.…”

“…4 The overall BRAF V600E mutation rate is approximately 30%, although the rate varies widely between studies. [4][5][6][7][8][9][10][11][12][13] The BRAF V600E mutation rate is important, given its treatment implications. Because virtually all ATC patients present with or develop distant metastases, 3,[14][15][16][17][18] ATC must be treated as a systemic disease; however, the efficacy of conventional chemotherapy in ATC patients is low.…”