Hürthle Cell Carcinomas Exhibit Widespread Loss of Heterozygosity

Hürthle cell carcinomas (HCC) arise from thyroid follicular cells and represent approximately 3% of all thyroid cancers. They are largely refractory to radioactive iodine and have poorer outcomes than other thyroid tumors. HCCs are characterized by an excessive accumulation of dysfunctional mitochondria, but the underlying molecular and genomic drivers are not well understood. To address this deficiency, Gopal, Kübler, and colleagues and Ganly and colleagues comprehensively characterized the somatic and mitochondrial genome of HCC in two independent studies. Gopal, Kübler, and colleagues performed exome sequencing of 70 HCC specimens (including primary tumors, distant metastases, and locoregional recurrences) from 41 patients along with matched DNA from blood or adjacent normal thyroid tissue. This analysis identified recurrent alterations in DAXX, TP53, NRAS, NF1, CDKN1A, ARHGAP35, and the TERT promoter. Further, alterations in the mitochondrial DNA (mtDNA) affecting genes encoding components of complex I occurred in 60% of patients. DNA copy-number analysis revealed widespread chromosomal loss that resulted in loss of heterozygosity (LOH) across most of the genome, resulting in a near-haploid state in the majority of the tumors that was associated with poor outcome. Despite the widespread chromosomal losses, chromosomal content was stable during metastatic progression. Similar results were obtained by Ganly and colleagues, who performed whole-exome and RNA sequencing of paired tumor and normal DNA from 56 patients with HCC, 24 with minimally invasive disease and 32 with widely invasive disease. Recurrent somatic mutations affected genes in the RTK/RAS/AKT/mTOR pathway, DNA damage and repair genes, epigenetic modifiers, and the TERT promoter, and several structural variants were detected including a TMEM233–PRKAB1 fusion gene. mtDNA mutations were enriched in genes that encode complex I subunits. Widespread LOH was also observed as well as whole-chromosomal duplication involving chromosomes 5 and 7. Collectively, these studies elucidate the molecular and genomic drivers of HCC.

Gopal RK, Kübler K, Calvo SE, Polak P, Livitz D, Rosebrock D, et al. Widespread chromosomal losses and mitochondrial DNA alterations as genetic drivers in Hürthle cell carcinoma. Cancer Cell 2018;34:242–55.

Ganly I, Makarov V, Deraje S, Dong Y, Reznik E, Seshan V, et al. Integrated genomic analysis of Hürthle cell cancer reveals oncogenic drivers, recurrent mitochondrial mutations, and unique chromosomal landscapes. Cancer Cell 2018;34:256–70.

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