Mitochondrial Proteomic Characterization of Thyroid Oncocytic Tumors: Diagnostic Potential of IDH2 as a Biomarker

Background and objective

Oncocytic thyroid neoplasm (OTN), also known as Hürthle cell tumor, is characterized by the abundant expression of mitochondria and is typically insensitive to radioactive iodine treatment. Compared to canonical thyroid cancer, oncocytic thyroid carcinoma (OTC) exhibits more aggressive biological behavior with a higher rate of lymph nodes and distant organs. Our 8-gene panel results indicate a low frequency of driver gene mutations of OTN. Hence, we explore the alterations based on the proteome.

Preliminary Data

To identify oncocytic protein features, we initially analyzed the proteome data from the Singapore dataset (N=64) which we published previously. Proteomic data were obtained by data-independent acquisition mode and searched through DIA-NN (1.8.1) against a thyroid-specific spectral library containing 136,821 precursors and 10,547 proteins. We next filtered the protein matrix by extracting proteins only expressed in mitochondria (n=386). To get robust protein features, we compared oncocytic adenomas versus non-oncocytic adenomas and oncocytic carcinomas versus non-oncocytic carcinomas through three statistical testing methods. As a result, 64 proteins were distilled. The pathway enrichment analysis showed the generation of precursor metabolites and energy was altered most.

Upon a closer examination of the data, we discovered that four out of five IDH family proteins exhibited a remarkable upregulation, exceeding a four-fold change. Notably, IDH2, a classical drug target protein, not only serves as a marker to distinguish oncocytic cells from non-oncocytic cells but also functions as a discriminator between malignant and benign oncocytic tumors. This observation aligns positively with the malignancy grade, indicating its potential diagnostic significance. Furthermore, our proteomics findings, based on mass spectrometry, were corroborated by immunohistochemistry in an independent cohort of 80 samples, reinforcing the reliability of our observations.

Novel Aspect

We have established a scoring system based on 64 mitochondrial proteins, which serves as a quantitative measure for thyroid oncocytic character. Furthermore, we propose that the protein marker IDH2 holds significant translational potential, promising to be a clinically valuable diagnostic tool.