Unique mutation patterns in anaplastic thyroid cancer identified by comprehensive genomic profiling

Abstract

Introduction Anaplastic thyroid cancer (ATC) is a highly aggressive thyroid cancer. Those ATC with genomic alterations (GAs) in TSC2, ALK, and BRAF may respond to targeted therapies. Methods Comprehensive genomic profiling on 90 ATC specimens identified base substitutions, short insertions and deletions, amplifications, copy number alterations, and genomic rearrangements in up to 315 cancer‐related genes and 28 genes commonly rearranged in cancer. Results Median patient age was 65 (range, 33‐86) years, 50 patients were male. There was a mean of 4.2 GA per case, range 1‐11. The most common GA were TP53 (66%), BRAF (34%), TERT (32%), CDKN2A (32%), and NRAS (26%). BRAF V600E and NRAS/HRAS/KRAS alteration were mutually exclusive. BRAF, CDKN2A, PIK3CA, and JAK2 were more frequent in patients >70 years of age; while myc, PTEN, and NRAS were more common in those ≤50 years. Conclusion ATC shows many GA with potential therapeutic significance and suggesting different molecular pathways can lead to ATC.

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

“…RAS mutation rate in ATC was reported ranging from 18% to 44.4%. In our cohort, N-RAS mutation was the most frequent (eight cases, 29.6%) among the three RAS subtypes, concordant with findings in previous reports [9,13,15,16]. K-RAS mutation was present in three cases (11.1%), while H-RAS mutation was not detected.…”

“…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

“…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.…”

“…For example, a higher BRAF V600E mutation rate in ATC has been found to be associated with older patient age. 7,12 Additionally, the BRAF V600E mutation rate could be due to differences in genetic background or iodine intake. The highest reported BRAF V600E mutation rate in ATC is 91% and was reported in a cohort in Korea, 6 where the prevalence of the BRAF V600E mutation in PTC is higher than it is in other geographical regions.…”

“…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.…”