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.

Recurrent ZFX mutations in human sporadic parathyroid adenomas

“…This MEN1 intragenic mutation frequency of ~11% is in agreement with earlier literature, which found a range between 12-20% [11][12][13], and contrasts with recent suggestions that the frequency might be considerably higher (up to 35-40%) [8,9,[17][18][19][20]. No mutations in genes recently proposed to be implicated in parathyroid adenoma tumorigenesis, such as CTTNB1, EZH2 and POT1, were identified, attesting to the rarity of these candidate genes' potential contributions [21].…”

“…However, these derangements occur, collectively, in a minority of these tumors [2,3,7], and even when present are likely to cooperate with other driver lesions; thus multiple additional targets for tumorigenic mutation and future therapeutics undoubtedly exist. Indeed, studies of the genomes of parathyroid adenomas using a variety of methods have revealed a complex and heterogeneous landscape of chromosomal and DNA sequence level changes [8][9][10][11][12][13]. Identification of novel, recurrently altered genes has been difficult due to a low frequency of mutation observed in candidate genes and the limited number of cases examined [8,9].…”

Radiological considerations and surgical planning in the treatment of giant parathyroid adenomas

“…3 Indeed, in a study published by Sulaiman et al in 2012, the genetic characterisation of sporadic parathyroid adenomas weighing >4g revealed specific genomic features that correlated positively with PTH levels and therefore parathyroid hyperfunction. 4 The present case was that of a true giant parathyroid adenoma, both in terms of its size and weight, associated with severe hypercalcaemia and extremely high PTH levels. These features raised the suspicion of malignancy and necessitated urgent surgery.…”

Evaluation of preoperative ultrasonographic and biochemical features of patients with aggressive parathyroid disease: is there a reliable predictive marker?

“…Moreover Sulaiman and cols. showed that most of larger parathyroid lesions were benign PAs associated with specific genomic features (32).…”