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 BRAFV600E 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.

Heterogeneity of Thyroid Cancer

“…Apart from the above-mentioned genetic alterations, several other genes have been demonstrated to be mutated in FTC, albeit with a much lower frequency, including PI3CA , PTEN , DICER1 , EZH1 , and SPOP [80, 81]. Many of these genes are involved in the PI3K/PTEN/AKT pathway, which is believed to be the key signalling pathway in FTC development [82].…”

Non-coding RNAs: long non-coding RNAs and microRNAs in endocrine-related cancers

“…The identity and targets of miRNAs dysregulated in PTC and follicular thyroid carcinoma (FTC) have been recently reviewed (Celano, et al 2017;Lima, et al 2017;Pallante, et al 2013;Pishkari, et al 2017;Saiselet, et al 2016;Yoo, et al 2016). miRNAs upregulated in PTC include miR-21, miR-31, miR-99-3p, miR-128a, miR-128b, miR-139, miR-141, miR-146a, miR146b-3p, miR-146b-5p, miR-155, miR-181a, miR-181b, miR-187, miR-191, miR-200a, miR200b, miR-200c, miR-220, miR-221, miR-222, miR-222-5p, miR-224, miR-375, miR-551b (Pallante et al 2013).…”

Cribriform-morular variant of papillary thyroid carcinoma: a distinctive type of thyroid cancer

“…The works of the Cancer Genome Atlas (TCGA) research network have revolutionized our understanding of molecular pathogenesis of thyroid carcinoma (Cancer Genome Atlas Research Network 2014, Yoo et al 2016). The findings also resulted in a new classification of thyroid tumours that is incorporated in the fourth edition of the WHO classification of endocrine tumours (Lam 2017).…”