High-resolution genomic profiling of thyroid lesions uncovers preferential copy number gains affecting mitochondrial biogenesis loci in the oncocytic variants.

Oncocytic change is the result of aberrant mitochondrial hyperplasia, which may occur in both neoplastic and non-neoplastic cells and is not infrequent in the thyroid. Despite being a well-characterized histologic phenotype, the molecular causes underlying such a distinctive cellular change are poorly understood. To identify potential genetic causes for the oncocytic phenotype in thyroid, we analyzed copy number alterations in a set of oncocytic (n=21) and non-oncocytic (n=20) thyroid lesions by high-resolution microarray-based comparative genomic hybridization (aCGH). Each group comprised lesions of diverse histologic types, including hyperplastic nodules, adenomas and carcinomas. Unsupervised hierarchical clustering of categorical aCGH data resulted in two distinct branches, one of which was significantly enriched for samples with the oncocytic phenotype, regardless of histologic type. Analysis of aCGH events showed that the oncocytic group harbored a significantly higher number of genes involved in copy number gains, when compared to that of conventional thyroid lesions. Functional annotation demonstrated an enrichment for copy number gains that affect genes encoding activators of mitochondrial biogenesis in oncocytic cases but not in their non-oncocytic counterparts. Taken together, our data suggest that genomic alterations may represent additional/alternative mechanisms underlying the development of the oncocytic phenotype in the thyroid.