Gene expression of parathyroid tumors: molecular subclassification and identification of the potential malignant phenotype.
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 beta 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.
Haven
Carola J
CJ
Laboratory of Cancer Genetics and Bioinformatics Special Program, Van Andel Research Institute, Grand Rapids, Michigan, USA.
Howell
Viive M
VM
Eilers
Paul H C
PH
Dunne
Robert
R
Takahashi
Masayuki
M
van Puijenbroek
Marjo
M
Furge
Kyle
K
Kievit
Job
J
Tan
Min-Han
MH
Fleuren
Gert Jan
GJ
Robinson
Bruce G
BG
Delbridge
Leigh W
LW
Philips
Jeanette
J
Nelson
Anne E
AE
Krause
Ulf
U
Dralle
Henning
H
Hoang-Vu
Cuong
C
Gimm
Oliver
O
Morreau
Hans
H
Marsh
Deborah J
DJ
Teh
Bin T
BT
D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D005810:Multigene Family; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010282:Parathyroid Neoplasms / Q000145:classification* / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics; D015854:Up-Regulation
C105373:MEN1 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins