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Gene Expression of Parathyroid Tumors

Molecular Subclassification and Identification of the Potential Malignant Phenotype

¹ Laboratory of Cancer Genetics and ² Bioinformatics Special Program, Van Andel Research Institute, Grand Rapids, Michigan; Departments of ³ Pathology, ⁴ Medical Statistics, and ⁵ Surgery, Leiden University Medical Center, Leiden, the Netherlands; ⁶ Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Sydney, New South Wales, Australia; ⁷ Commonwealth Scientific and Industrial Research Organisation, Mathematical and Information Sciences, North Ryde, Sydney, Australia; ⁸ Department of Surgery, Royal North Shore Hospital, New South Wales, Australia; ⁹ Pacific Laboratory Medicine Services, Royal North Shore Hospital and Department of Pathology, University of Sydney; Departments of ¹⁰ Pathology and ¹¹ General, Visceral and Vascular Surgery, Martin Luther University, Halle-Wittenberg, Germany

Parathyroid tumors are heterogeneous, and diagnosis is often difficult using histologic and clinical features.

We have undertaken expression profiling of 53 hereditary and sporadic parathyroid tumors to better define the molecular genetics of parathyroid tumors. A class discovery approach identified three distinct groups: (1) predominantly hyperplasia cluster, (2) HRPT2/carcinoma cluster consisting of sporadic carcinomas and benign and malignant tumors from Hyperparathyroidism-Jaw Tumor Syndrome patients, and (3) adenoma cluster consisting mainly of primary adenoma and MEN 1 tumors. Gene sets able to distinguish between the groups were identified and may serve as diagnostic biomarkers. We demonstrated, by both gene and protein expression, that Histone 1 Family 2, amyloid ß precursor protein, and E-cadherin are useful markers for parathyroid carcinoma and suggest that the presence of a HRPT2 mutation, whether germ-line or somatic, strongly influences the expression pattern of these 3 genes. Cluster 2, characterized by HRPT2 mutations, was the most striking, suggesting that parathyroid tumors with somatic HRPT2 mutation or tumors developing on a background of germ-line HRPT2 mutation follow pathways distinct from those involved in mutant MEN 1-related parathyroid tumors. Furthermore, our findings likely preclude an adenoma to carcinoma progression model for parathyroid tumorigenesis outside of the presence of either a germ-line or somatic HRPT2 mutation. These findings provide insights into the molecular pathways involved in parathyroid tumorigenesis and will contribute to a better understanding, diagnosis, and treatment of parathyroid tumors.

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