| Summary: | Thyroid cancer is the most common endocrine malignancy. However, the cytological diagnosis of follicular thyroid carcinoma (FTC), Hürthle cell carcinoma (HCC), and follicular variant of papillary thyroid carcinoma (FVPTC) and their benign counterparts is a challenge for preoperative diagnosis. Nearly 20–30% of biopsied thyroid nodules are classified as having indeterminate risk of malignancy and incur costs to the health care system. Based on that, 120 patients were screened for the main driver mutations previously described in thyroid cancer. Subsequently, 14 mutation-negative cases that are the main source of diagnostic errors (FTC, HCC, or FVPTC) underwent RNA-Sequencing analysis. Somatic variants in candidate driver genes (<i>ECD, NUP98,</i><i>LRP1B, NCOR1, ATM, SOS1</i>, and <i>SPOP</i>) and fusions were described. <i>NCOR1</i> and <i>SPOP</i> variants underwent validation. Moreover, expression profiling of driver-negative samples was compared to 16 BRAF V600E, <i>RAS</i>, or <i>PAX8-PPARg</i> positive samples. Negative samples were separated in two clusters, following the expression pattern of the <i>RAS/PAX8-PPARg</i> or BRAF V600E positive samples. Both negative groups showed distinct BRS, ERK, and TDS scores, tumor mutation burden, signaling pathways and immune cell profile. Altogether, here we report novel gene variants and describe cancer-related pathways that might impact preoperative diagnosis and provide insights into thyroid tumor biology.
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