Integrated Genomic Analysis of Hürthle Cell Cancer Reveals Oncogenic Drivers, Recurrent Mitochondrial Mutations, and Unique Chromosomal Landscapes

Abstract

The molecular foundations of Hürthle 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 these tumors exhibit a wide range of recurrent mutations. Notably, we report a 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 fusion genes and disrupted signaling pathways that may drive disease pathogenesis.

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“…PAX8/PPARG rearrangements occur in approximately 8% of FA, 10% of NIFTP, 1% of follicular variant PTC and 20–30% of FTC. EIF1AX mutation can be found in hyperplastic nodules, FA, NIFTP, FTC, PTC, PDC, ATC and Hürthle cell carcinomas . Cytogenetic changes occur in 50% of FA and 65% of FTC .…”

“…Somatic genomic alterations in Hürthle cell carcinomas are different from those in PTC and FTC. Hürthle cell carcinomas have MADCAM1, EIF1AX, NRAS, DAXX, PT53 and NF1 mutations , but no BRAF mutations and a lower frequency of NRAS mutation than FTC . Somatic recurrent mitochondrial mutations occur in 71% of Hürthle cell carcinomas.…”

“…Somatic recurrent mitochondrial mutations occur in 71% of Hürthle cell carcinomas. Unique chromosomal landscapes in Hürthle cell carcinomas involve whole‐chromosome duplication of chromosomes 5 and 7, and widespread loss of chromosomes resulting in near‐haploid chromosomal content …”

“…EIF1AX mutation can be found in hyperplastic nodules, FA, NIFTP, FTC, PTC, PDC, ATC and H€ urthle cell carcinomas. 90,[199][200][201][202] Cytogenetic changes occur in 50% of FA and 65% of FTC. 1 PTEN and PIK3CA mutations also occur in 5% of FA and up to 10% of FTC.…”

“…H€ urthle cell carcinomas have MADCAM1, EIF1AX, NRAS, DAXX, PT53 and NF1 mutations, but no BRAF mutations and a lower frequency of NRAS mutation than FTC. 201,205 Somatic recurrent mitochondrial mutations occur in 71% of H€ urthle cell carcinomas. Unique chromosomal landscapes in H€ urthle cell carcinomas involve wholechromosome duplication of chromosomes 5 and 7, and widespread loss of chromosomes resulting in near-haploid chromosomal content.…”