title: Genetic characterization of large parathyroid adenomas.
abstract: In this study, we genetically characterized parathyroid adenomas with large glandular weights, for which independent observations suggest pronounced clinical manifestations. Large parathyroid adenomas (LPTAs) were defined as the 5% largest sporadic parathyroid adenomas identified among the 590 cases operated in our institution during 2005-2009. The LPTA group showed a higher relative number of male cases and significantly higher levels of total plasma and ionized serum calcium (P<0.001). Further analysis of 21 LPTAs revealed low MIB1 proliferation index (0.1-1.5%), MEN1 mutations in five cases, and one HRPT2 (CDC73) mutation. Total or partial loss of parafibromin expression was observed in ten tumors, two of which also showed loss of APC expression. Using array CGH, we demonstrated recurrent copy number alterations most frequently involving loss in 1p (29%), gain in 5 (38%), and loss in 11q (33%). Totally, 21 minimal overlapping regions were defined for losses in 1p, 7q, 9p, 11, and 15q and gains in 3q, 5, 7p, 8p, 16q, 17p, and 19q. In addition, 12 tumors showed gross alterations of entire or almost entire chromosomes most frequently gain of 5 and loss of chromosome 11. While gain of 5 was the most frequent alteration observed in LPTAs, it was only detected in a small proportion (4/58 cases, 7%) of parathyroid adenomas. A significant positive correlation was observed between parathyroid hormone level and total copy number gain (r=0.48, P=0.031). These results support that LPTAs represent a group of patients with pronounced parathyroid hyperfunction and associated with specific genomic features.
authors.affiliation: Medical Genetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital CMM L8:01, SE-171 76 Stockholm, Sweden.
authors.forename: Luqman
authors.initials: L
authors.lastname: Sulaiman
authors.forename: Inga-Lena
authors.initials: IL
authors.lastname: Nilsson
authors.forename: C Christofer
authors.initials: CC
authors.lastname: Juhlin
authors.forename: Felix
authors.initials: F
authors.lastname: Haglund
authors.forename: Anders
authors.initials: A
authors.lastname: Höög
authors.forename: Catharina
authors.initials: C
authors.lastname: Larsson
authors.forename: Jamileh
authors.initials: J
authors.lastname: Hashemi
mesh_terms: D000236:Adenoma / Q000097:blood / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics; D002118:Calcium / Q000097:blood; D055028:Comparative Genomic Hybridization; D005260:Female; D018628:Gene Dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010281:Parathyroid Hormone / Q000097:blood; D010282:Parathyroid Neoplasms / Q000097:blood / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D053468:CARD Signaling Adaptor Proteins; C478017:CARD6 protein, human; C454900:CDC73 protein, human; C105373:MEN1 protein, human; D010281:Parathyroid Hormone; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D002118:Calcium