Abstract
Hürthle cell thyroid carcinoma (HTC) accounts for 3–5% of all thyroid malignancies. Widely invasive HTC is characterized by poor prognosis and limited responsiveness to standard therapy with radioiodine. The molecular landscape of HTC is significantly different from the genetic signature seen in other forms of thyroid cancer. We performed a comprehensive literature review on the association between the molecular features of HTC and cancer metabolism. We searched the Pubmed, Embase, and Medline databases for clinical and translational studies published between 1980 and 2020 in English, coupling “HTC” with the following keywords: “genomic analysis”, “mutations”, “exome sequencing”, “molecular”, “mitochondria”, “metabolism”, “oxidative phosphorylation”, “glycolysis”, “oxidative stress”, “reactive oxygen species”, and “oncogenes”. HTC is characterized by frequent complex I mitochondrial DNA mutations as early clonal events. This genetic signature is associated with the abundance of malfunctioning mitochondria in cancer cells. HTC relies predominantly on aerobic glycolysis as a source of energy production, as oxidative phosphorylation-related genes are downregulated. The enhanced glucose utilization by HTC is used for diagnostic purposes in the clinical setting for the detection of metastases by fluorodeoxyglucose positron emission tomography (FGD-PET/CT) imaging. A comprehensive metabolomic profiling of HTC in association with its molecular landscape might be necessary for the implementation of tumor-specific therapeutic approaches.
Highlights
Differentiated thyroid cancer (DTC) arises from the follicular cells of the thyroid gland and is the fifth most common malignancy in women [1,2,3]
The dysregulated mitochondrial function leading to excessive ROS production and downregulated oxidative phosphorylation (OXPHOS) which has been observed in Hürthle cell thyroid cancer (HTC) is associated with the compensatory upregulation of aerobic glycolysis [65,66,67]
HTC is distinct from other cancers, as demonstrated by the extensive mitochondrial DNA (mtDNA) mutations as well as the whole chromosome losses
Summary
Differentiated thyroid cancer (DTC) arises from the follicular cells of the thyroid gland and is the fifth most common malignancy in women [1,2,3]. HTC is characterized by a capsular and vascular invasion, while benign Hürthle cell adenoma lacks invasive features [4]. The main distinction between benign Hürthle cell adenoma and HTC is based on copy number alterations and a nearly complete genome haploidization specific to HTC, as identified by ThyroSeq v3.0 [16]. An increasing number of indeterminate nodules have been determined as benign in nature [17,18] This has led to a significant improvement in the specificity and positive predictive value of the test, with the predicted ability to avoid up to 60% of unnecessary surgeries for benign conditions [8]. The goal of this study was to provide a comprehensive review of the molecular landscape of HTC, the widely invasive form of HTC
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