Mutation profiles of follicular thyroid tumors by targeted sequencing

Abstract

Background One of the major challenges remaining in the classification of thyroid tumor is the determination of whether a nodule is benign or malignant. We aimed to characterize the mutational profiles of follicular thyroid tumor and to identify markers with potential diagnostic and prognostic implications. Methods Targeted sequencing with a panel of 18 thyroid cancer-related genes was performed on 48 tissue samples from follicular thyroid adenoma (FTA), 32 follicular tumors of uncertain malignant potential (FT-UMP), 17 well-differentiated tumors of uncertain malignant potential (WDT-UMP) and 53 samples from follicular thyroid carcinoma (FTC). The correlation of mutation profiles and clinicopathological features and prognosis were also analyzed. Results We identified 95 nonsilent mutations spanning 14 genes. Specifically, TERT promoter (TERTp) mutations were exclusively detected in FTC. A total of 80% EIF1AX exon 2 mutations (4/5) and 75% TSHR mutations (3/4) occurred in FTA, whereas the rest of them occurred in FT-UMP. KRAS mutations and TP53 mutations were only presented in borderline or malignant tumors. H/N-RAS mutations were detected in all four subtypes, but were most commonly found in WDT-UMP ( p = 0.031). All N-RAS mutations were located at codon 61. BRAF V600E and RET fusion were absent in the entire cohort. In FTC cases, EIF1AX mutations were all located at intron 5/exon 6 and correlated with advanced disease ( p = 0.032). Both EIF1AX and TERTp mutations predicted shorter disease-free survival ( p = 0.007, p = 0.024, respectively). Further analysis revealed that TERTp mutations were correlated with shorter disease-free survival in patients with minimally invasive /encapsulated angioinvasive FTC ( p = 0.017), but not in those with widely invasive FTC ( p = 0.297). Conclusion TERTp , EIF1AX, TSHR, H/N/K-RAS and TP53 mutations may have diagnostic or prognostic potential in follicular thyroid tumors. TERTp mutations may predict a poor outcome in patients with minimally invasive/encapsulated angioinvasive FTC.

Amplicon-Based NGS Panels for Actionable Cancer Target Identification in Follicular Cell-Derived Thyroid Neoplasia

“…The similarity of the somatic mutation profiles among FAs and FTCs supports the point raised regarding FTCs more likely being a continuum of FAs rather than a distinct diagnostic entity and will probably add to the ongoing scientific discussion (20,21). Recent studies have explored the possible correlation of the somatic mutation signature and burden to histopathological diagnostic classes and found no substantial correlation (2,15,22,23). However, two of the studies succeeded in showing a significant correlation between patient prognosis and mutational signature and/or overall mutation load (15,23).…”

“…Recent studies have explored the possible correlation of the somatic mutation signature and burden to histopathological diagnostic classes and found no substantial correlation (2,15,22,23). However, two of the studies succeeded in showing a significant correlation between patient prognosis and mutational signature and/or overall mutation load (15,23). In brief, the study by Nicolson et al (15) correlated the somatic signature of 39 FTC to both diagnosis and prognosis and found that mutation burden was associated to a worse prognosis, independent of histopathological classification.…”

Thyroid Tumor: Investigating MicroRNA-21 Gene Suppression in FTC and FTA

“… 7 The histopathological interpretation of capsular or vascular invasion varies and depends on the discretion of pathologists which leads to imprecise classification. 5 This led to calls that classification based on discretion should be discouraged to allow for careful and adequate clinical classification. 8 …”

Next generation sequencing based detection of 15 target genes mutations in papillary thyroid carcinoma

“…5,6 Recently, published literature increasingly suggested that somatic mutations in BRAF, HRAS, KRAS, NRAS, TERT, RET, PIK3CA, PTEN, TP53, CTNNB1,AKT1, GNAS, PAX8/PPARγ, NTRK1, and TSHR genes have been associated with diagnosis and treatment of TC. [7][8][9][10][11][12][13][14][15][16] Next generation sequencing (NGS) is a newlydeveloped technique offered a cost-effective approach for detecting multiple genetic alterations and provided quantitative assessment of mutation frequency. 17,18 Therefore, a panel designed to these 15 target genes was used to detect molecular alterations by NGS in PTC.…”

“…In the past, single gene assays, such as BRAF V600E mutation, have been commonly used for finding molecular alterations by Sanger sequence, immunohistochemistry, and real time PCR in PTC 5,6 . Recently, published literature increasingly suggested that somatic mutations in BRAF, HRAS, KRAS, NRAS, TERT, RET, PIK3CA, PTEN, TP53, CTNNB1,AKT1, GNAS, PAX8/PPARγ, NTRK1, and TSHR genes have been associated with diagnosis and treatment of TC 7‐16 . Next generation sequencing (NGS) is a newly‐developed technique offered a cost‐effective approach for detecting multiple genetic alterations and provided quantitative assessment of mutation frequency 17,18 .…”