Mitonuclear genotype remodels the metabolic and microenvironmental landscape of Hürthle cell carcinoma

Abstract

Hürthle cell carcinomas (HCCs) display two exceptional genotypes: near-homoplasmic mutation of mitochondrial DNA (mtDNA) and genome-wide loss of heterozygosity (gLOH). To understand the phenotypic consequences of these genetic alterations, we analyzed genomic, metabolomic, and immunophenotypic data of HCC and other thyroid cancers. Both mtDNA mutations and profound depletion of citrate pools are common in HCC and other thyroid malignancies, suggesting that thyroid cancers are broadly equipped to survive tricarboxylic acid cycle impairment, whereas metabolites in the reduced form of NADH-dependent lysine degradation pathway were elevated exclusively in HCC. The presence of gLOH was not associated with metabolic phenotypes but rather with reduced immune infiltration, indicating that gLOH confers a selective advantage partially through immunosuppression. Unsupervised multimodal clustering revealed four clusters of HCC with distinct clinical, metabolomic, and microenvironmental phenotypes but overlapping genotypes. These findings chart the metabolic and microenvironmental landscape of HCC and shed light on the interaction between genotype, metabolism, and the microenvironment in cancer.

Facilitation of Definitive Cancer Diagnosis With Quantitative Molecular Assays of BRAF V600E and TERT Promoter Variants in Patients With Thyroid Nodules

“…Cancer arises from genomic alterations that can lead to dysregulation of gene expression and drive oncogenesis within and across tumor types . Significant advances have been made in the understanding of cancer molecular pathogenesis, including genetic and epigenetic alterations . Molecular assays, such as real-time polymerase chain reaction (PCR) and next-generation sequencing (NGS), have arisen to detect genomic changes in tumors as novel cancer diagnostic approaches with great potential in the preoperative stratification of malignancy or benignity in thyroid nodules .…”

Mitochondrial-encoded complex I impairment induces a targetable dependency on aerobic fermentation in Hürthle cell carcinoma of the thyroid

“…These results suggest that ETC function was below a threshold required for viability following LDH inhibition or culture in glucose-free or galactose-containing media. Analysis of glucose metabolism in XTC.UC1 revealed that these cells display defects in glucose oxidation and recent profiling of patient-derived HTC tumors identified metabolic changes consistent with ETC dysfunction (Ganly et al ., 2022). Therefore, HTC tumors that lack damaging near-homoplasmic mtDNA mutations might harbor sufficient disruption of oxidative phosphorylation and glucose metabolism to be sensitized to LDH inhibition.…”

“…Mitochondrial accumulation and evidence of metabolic rewiring are defining features of HTC, yet approximately 40% of HTC tumors do not harbor discrete mutations in complex I subunits (Ganly et al, 2022; Ganly et al ., 2018; Ganly and McFadden, 2019; Gopal et al ., 2018; McFadden and Sadow, 2021). This raises the question whether all HTC tumors exhibit functional ETC impairment.…”

Molecular Alterations and Comprehensive Clinical Management of Oncocytic Thyroid Carcinoma

“…Studies of somatic copy number alterations suggest that the wide chromosome instability observed in OTC may be associated with altered DNA damage repair, possibly related to a metabolic reprogramming and imbalance of ROS intracellular levels . Interestingly, gLOH was found to be associated with a depletion in immune cell infiltration, indicating that gLOH could confer a selective advantage partially through suppression of cytotoxic immune responses …”