Comprehensive Analysis of the Transcriptional and Mutational Landscape of Follicular and Papillary Thyroid Cancers

Abstract

Follicular thyroid carcinoma (FTC) and benign follicular adenoma (FA) are indistinguishable by preoperative diagnosis due to their similar histological features. Here we report the first RNA sequencing study of these tumors, with data for 30 minimally invasive FTCs (miFTCs) and 25 FAs. We also compared 77 classical papillary thyroid carcinomas (cPTCs) and 48 follicular variant of PTCs (FVPTCs) to observe the differences in their molecular properties. Mutations in H/K/NRAS, DICER1, EIF1AX, IDH1, PTEN, SOS1, and SPOP were identified in miFTC or FA. We identified a low frequency of fusion genes in miFTC (only one, PAX8–PPARG), but a high frequency of that in PTC (17.60%). The frequencies of BRAF ^V600E and H/K/NRAS mutations were substantially different in miFTC and cPTC, and those of FVPTC were intermediate between miFTC and cPTC. Gene expression analysis demonstrated three molecular subtypes regardless of their histological features, including Non– BRAF–Non– RAS (NBNR), as well as BRAF–like and RAS–like. The novel molecular subtype, NBNR, was associated with DICER1, EIF1AX, IDH1, PTEN, SOS1, SPOP, and PAX8–PPARG. The transcriptome of miFTC or encapsulated FVPTC was indistinguishable from that of FA, providing a molecular explanation for the similarly indolent behavior of these tumors. We identified upregulation of genes that are related to mitochondrial biogenesis including ESRRA and PPARGC1A in oncocytic follicular thyroid neoplasm. Arm-level copy number variations were correlated to histological and molecular characteristics. These results expanded the current molecular understanding of thyroid cancer and may lead to new diagnostic and therapeutic approaches to the disease.

Author Summary

Recently, The Cancer Genome Atlas proposed an improved classification of the subtypes of papillary thyroid carcinoma (PTC) based on gene expression profiles, which better represents cell signaling and differentiation. However, a molecular characterization of follicular thyroid carcinoma (FTC), which has a greater tendency for hematogenous spread to lung and bone is not yet fully elucidated. In this study, we describe the first RNA sequencing data of minimally invasive FTC (miFTC) and benign follicular adenoma (FA), which cause diagnostic difficulties due to their similar histological features. Additionally, classical PTC and follicular variant of PTC (FVPTC) were sequenced to compare their transcriptional and mutational landscape. BRAF, H/K/NRAS, fusion genes, and copy number variations were associated with tumor histology. Based on gene expression profiles, thyroid tumors were classified as three molecular subtypes regardless of histological subtypes, BRAF–like, RAS–like, and Non– BRAF–Non– RAS. In particular, we found identical gene expression profiles between miFTC, FA, and encapsulated FVPTC. Oncocytic follicular thyroid tumors have gene expression signatures related to mitochondrial biogenesis including ESRRA and PPARGC1A. These results expanded the current molecular understanding of thyroid cancer to its follicular types.