Clinical utility of EZH1 mutations in the diagnosis of follicular-patterned thyroid tumors

Abstract

Follicular-patterned tumors of the thyroid gland are characterized by a predominantly follicular growth pattern. They frequently harbor RAS mutations, not BRAF mutations. Technological advances in molecular testing have discovered novel RAS-type mutations. However, clinical significance of these mutations remains unknown. We investigated the prevalence and clinical impact of mutations of BRAF, NRAS, HRAS, KRAS, EZH1, EIF1AX, and TERT genes by Sanger sequencing in a series of 201 follicular-patterned thyroid tumors including follicular adenoma (n = 40), Hürthle cell adenoma (n = 54), noninvasive follicular thyroid neoplasms with papillary-like nuclear features (n = 50), follicular thyroid carcinoma (n = 40), Hürthle cell carcinoma (n = 10), and poorly differentiated thyroid carcinoma arising in a well-differentiated follicular neoplasm (n = 7), and 120 classic papillary carcinoma. Two hotspots of EZH1 mutations were only found in RAS-negative follicular-patterned tumors. EZH1 mutations were detected in 3% of follicular adenoma and in 20% of Hürthle cell adenoma, and one minimally invasive Hürthle cell carcinoma. Thyroid tumors with EZH1 mutations reported in the literature were benign in most cases. Otherwise, they were minimally invasive or noninvasive cancer. EIF1AX mutation was found in one follicular adenoma. We confirmed the presence of RAS mutations and BRAF K601E mutation in benign, borderline, and malignant follicular-patterned tumors. No BRAF V600E was found in all follicular-patterned tumors. This study also confirmed the occurrence of TERT promoter mutations in high-risk thyroid cancers. These genetic markers can be used for the diagnostic purpose and risk stratification of thyroid nodules.

The new 4th edition World Health Organization classification for thyroid tumors, Asian perspectives

“…Hyperfunctioning FA has mutations in TSHR , GNAS and EZH1 genes . EZH1 mutations also occur in Hürthle cell adenoma and minimally invasive FTC . RAS mutations are frequent in NIFTP, as well as PAX8/PPARG and THADA//IGF2BP3 fusions .…”

“…203 EZH1 mutations also occur in H€ urthle cell adenoma and minimally invasive FTC. 204 RAS mutations are frequent in NIFTP, as well as PAX8/PPARG and THADA//IGF2BP3 fusions. 1,200 BRAF K601E and small insertions or deletions surrounding codon 600 of BRAF can occur, 93,200 but NIFTP should not have BRAF V600E , TERT or TP53 mutations, or RET/ PTC fusions, which have a risk of malignancy of nearly 100%.…”

VE1 Immunohistochemistry Improves the Limit of Genotyping for Detecting BRAFV600E Mutation in Papillary Thyroid Cancer

“…To validate the specificity of the VE1 antibody, we performed the VE1 IHC in 71 RAS-mutant non-PTC tumors including follicular neoplasms, Hürthle cell neoplasms, and poorly differentiated carcinomas that were employed in our previous study [53].…”

Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features: From Echography to Genetic Profile

“…Molecular tests are helpful but not required for NIFTP diagnosis. BRAFV600E, RET/PTC fusions or gene mutations such as TERT promoter or TP53 exclude a diagnosis of NIFTP (Nikiforov et al 2018), but it has been observed that if the morphological diagnostic criteria are strictly observed, these mutations are very unlikely to occur (Nikiforov et al 2016;Johnson and Sadow 2018;Jung et al 2018;Kim et al 2018a), apart from some exceptional cases (Kim et al 2018b).…”