Molecular genetic insights into sporadic primary hyperparathyroidism

Abstract

Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterized by dysregulation of parathyroid hormone release. The large majority of PHPT cases are attributable to sporadic, single-gland parathyroid adenoma, in which MEN1 and CCND1/cyclin D1 are the most well-established drivers of tumorigenesis. Sporadic parathyroid carcinoma, which appears to mostly arise through molecular pathways distinct from those causing benign parathyroid tumors, is rare and is most frequently driven by mutational inactivation of the CDC73 (HRPT2) tumor suppressor gene. Targeted investigation of suspected tumor driver genes, as well as unbiased whole-genome or exome sequencing of small cohorts, have revealed additional novel candidate tumor genes in sporadic parathyroid neoplasia, generally at modest or low mutational frequencies consistent with marked molecular genetic heterogeneity from tumor to tumor. The ability of these additional candidates to participate in the pathogenic process of driving parathyroid tumorigenesis in vivo largely remains to be demonstrated experimentally. This review will summarize the molecular genetic abnormalities identified to date in sporadic PHPT and discuss the strength of evidence for their proposed roles in parathyroid tumor formation.

Atypical parathyroid adenomas: challenging lesions in the differential diagnosis of endocrine tumors

“…Multiclonal tumor origin is the predominant mode of tumorigenesis of some cancer types, like colorectal cancer, whereas other tumors, such as many of the myeloid cell lineages, seem to rather have a monoclonal tumor origin. If parathyroid tumorigenesis would follow the multiclonal origin model we would expect that known molecular events characterizing parathyroid adenomas, that is 11q loss and/or MEN1 mutations, would also be present in carcinomas at a frequency ≥35% (Pardi et al 2013, Brewer et al 2019. The finding that such alterations occur at a very low frequency in parathyroid carcinoma suggests that most parathyroid cancers arise de novo, rather than evolve from a preexisting benign adenoma (Costa-Guda et al 2013, Brewer et al 2019.…”

“…As mentioned before, the prevalence of parathyroid carcinoma in these patients is much higher than in sporadic cases (up to 37 vs 1%, respectively). In this setting, rare patients have a parathyroid carcinoma that has been progressed from a benign or atypical parathyroid adenoma (Brewer et al 2019). However, as underlined in the pathology section, since the histological diagnosis of atypical adenomas and carcinomas could be very challenging, as to whether in HPT-JT, there is a true progression from benign to malignant phenotype remains unclear.…”

“…The oncosuppressor MEN1 gene and CCND1 oncogene have been clearly established as drivers of benign parathyroid tumorigenesis (Brewer et al 2019). A small subset of patients with parathyroid carcinoma carries MEN1 mutations and their frequency is much lower than that reported in sporadic parathyroid adenoma (6 vs 35%, respectively) (Brewer et al 2019).…”

“…The oncosuppressor MEN1 gene and CCND1 oncogene have been clearly established as drivers of benign parathyroid tumorigenesis (Brewer et al 2019). A small subset of patients with parathyroid carcinoma carries MEN1 mutations and their frequency is much lower than that reported in sporadic parathyroid adenoma (6 vs 35%, respectively) (Brewer et al 2019). Loss-of-function MEN1 mutations have been searched for in ten atypical parathyroid adenomas and only one germline mutation (c.253A>T, p.127S) in exon 2 was detected in a MEN1 patient (Cetani et al 2002, Juhlin et al 2006, Mizusawa et al 2006, Sulaiman et al 2012a, Pal et al 2018.…”

“…Overexpression of cyclin D1 has been reported in about 65-90% of parathyroid carcinomas and in 18-40% of benign adenomas (Brewer et al 2019). Conversely, its overexpression in atypical adenomas ranges between 13 and 71% (Stojadinovic et al 2003, Cetani et al 2007, Sungu et al 2018.…”