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.
Medical Genetics Unit, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, S. Orsola-Malpighi Hospital Bologna, Italy.
Ivana
I
Kurelac
Department of Clinical, Diagnostic and Experimental Medicine (DIMES), University of Bologna, Section of Anatomic Pathology at Bellaria Hospital Bologna, Italy.
Dario
D
de Biase
Medical Genetics Unit, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, S. Orsola-Malpighi Hospital Bologna, Italy.
Claudia
C
Calabrese
Department of Clinical, Diagnostic and Experimental Medicine (DIMES), University of Bologna, S. Orsola-Malpighi Hospital Bologna, Italy.
Claudio
C
Ceccarelli
Department of Pathology, Memorial Sloan Kettering Cancer Center New York, NY, USA.
Charlotte Ky
CK
Ng
Department of Pathology, Memorial Sloan Kettering Cancer Center New York, NY, USA.
Raymond
R
Lim
Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research London, UK.
Alan
A
MacKay
Department of Pathology, Memorial Sloan Kettering Cancer Center New York, NY, USA.
Britta
B
Weigelt
Department of Farmacy and Biotechnology (FABIT), University of Bologna Bologna, Italy.
Anna Maria
AM
Porcelli
Department of Pathology, Memorial Sloan Kettering Cancer Center New York, NY, USA.
Jorge S
JS
Reis-Filho
Department of Clinical, Diagnostic and Experimental Medicine (DIMES), University of Bologna, Section of Anatomic Pathology at Bellaria Hospital Bologna, Italy.
Giovanni
G
Tallini
Medical Genetics Unit, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, S. Orsola-Malpighi Hospital Bologna, Italy.
Giuseppe
G
Gasparre
Thyroid oncocytic lesions; aCGH; mitochondrial biogenesis