Unravelling the Tumourigenesis Mechanisms of Oncocytic Cell Tumours: Discoveries from a Comparative Omics Study

Oncocytic cell tumours (OCTs), previously referred to as Hürthle cell tumours of the thyroid, are a subset of thyroid and endocrine neoplasms that pose diagnostic and therapeutic challenges owing to their unpredictable clinical behaviour. The transcriptomic and proteomic landscapes of OCTs remain poorly characterized compared with those of mitochondrion-rich neoplasms (MRNs: thyroid tumours with ≥75% oncocytic cells that share similar morphology but harbour nuclear driver mutations consistent with their respective histotypes rather than mitochondrial alterations).

We performed RNA and protein sequencing on 12 OCT samples and 6 MRNs. This study was prompted by the understanding that oncocytic morphology alone does not necessarily predict tumour behaviour.

RNA sequencing analysis identified 47 downregulated and 38 upregulated differentially expressed genes (DEGs) in OCTs relative to MRNs, with significant enrichment in pathways related to heme metabolism. Protein sequencing further revealed 20 under-expressed and 64 over-expressed differentially expressed proteins (DEPs) in OCTs. Notably, all oncocytic carcinomas formed a distinct cluster separate from the MRNs, indicating a unique proteomic profile.

Most of the DEPs were involved in three key cellular pathways: epigenetic regulation, the tumour microenvironment, and protein biogenesis, suggesting that these processes may underlie the distinctive morphology and behaviour of OCTs. These findings highlight the need for continued research into these molecular mechanisms to improve the diagnostic accuracy and develop targeted therapies for patients with OCTs.