Integrated genomic analysis of Hurthle cell carcinoma reveals novel oncogenic drivers, recurrent mitochondrial mutations, and unique chromosomal landscapes

The molecular foundations of Hurthle cell carcinoma (HCC) are poorly understood. Here, we describe a comprehensive genomic characterization of 56 primary HCC tumors that span the spectrum of tumor behavior. We elucidate the mutational profile and driver mutations and show that they exhibit a wide range of recurrent mutations, most of which have not previously been reported. Notably, we report an extremely high number of disruptive mutations to both protein-coding and tRNA-encoding regions of the mitochondrial genome. We reveal unique chromosomal landscapes that involve whole-chromosomal duplications of chromosomes 5 and 7 and widespread loss of heterozygosity arising from haploidization and copy number–neutral uniparental disomy. We also identify novel fusion genes and disrupted signaling pathways that may drive disease pathogenesis.