The Molecular Landscape of Hürthle Cell Thyroid Cancer Is Associated with Altered Mitochondrial Function—A Comprehensive Review

Abstract

<jats:p>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.</jats:p>

Maximizing Small Biopsy Patient Samples: Unified RNA-Seq Platform Assessment of over 120,000 Patient Biopsies

“…As shown in Figure 3 A, differences in mitochondrial gene expression were observed across different disease states, including lower expression in ILD TBBs compared with lung bronchoscopy brushing and biopsy samples. The application of mitochondrial content for diagnostic purposes is illustrated by the classification of thyroid tumors into the challenging subtype known as Hürthle cell neoplasms, which are characterized by an abundance of malfunctioning mitochondria [ 58 ]. We observed significantly higher expression of mitochondrial genes in thyroid FNA samples classified as Hürthle cell-positive based on the Afirma classifier ( Figure 3 B).…”

“…For example, detection and quantitation of both nuclear and mitochondrial transcripts increases the information available for diagnostic purposes. Chronic lymphocytic thyroiditis (benign), Hürthle cell adenomas (benign), and Hürthle cell carcinomas (malignant) are observed among thyroid nodules and are characterized by increased abundance of mitochondria relative to non-Hürthle nodules [ 58 ]. Differentiating which samples require surgery has been a long-standing clinical challenge.…”

Using BioPAX-Parser (BiP) to enrich lists of genes or proteins with pathway data

“…Noticeably, in the intersection between the top 10 enriched pathways from both data sets UCEC and GSE63678, only BIP identified as novel candidate risk pathways Ubiquitin mediated proteolysis pathway ( p value = ) and Oxidative phosphorylation pathway ( p value = ) and reticulum pathway . [ 132 – 134 ] and [ 95 ] describe the involvement of those pathways in TC, which were ignored by the other tools.…”

Thyroid cancer under the scope of emerging technologies

“…These numerous mitochondria result from mutations in mitochondrial DNA, mostly in genes encoding subunits of complex I of the electron transport chain, leading to decreased oxidative phosphorylation (Kumari, Adewale, and Klubo-Gwiezdzinska 2020;Máximo et al 2002). In addition, HCC show many chromosomal losses with genome-wide loss-of-heterozygosity, resulting in near-haploid cancer genomes (Corver et al 2018) often rescued by whole-genome doubling, and mutations in nuclear DNA involving several genes from the MAPK and PI3K signaling pathways, such as RAS, PTEN, PIK3CA or TSC1/2 (Ganly et al 2013;Gopal et al 2018).…”