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Objective  Primary hyperparathyroidism is most often caused by a sporadic single-gland parathyroid adenoma (PTA), a tumor type for which cyclin D1 is the only known and experimentally validated oncoprotein. However, the molecular origins of its frequent overexpression have remained mostly elusive. In this study, we explored a potential tumorigenic mechanism that could increase cyclin D1 stability through a defect in molecules responsible for its degradation.    Methods  We examined two tumor suppressor genes known to modulate cyclin D1 ubiquitination,  PRKN  and  FBXO4  ( FBX4 ), for evidence of classic two-hit tumor suppressor inactivation within a cohort of 82 PTA cases. We examined the cohort for intragenic inactivating and splice site mutations by Sanger sequencing and for locus-associated loss of heterozygosity (LOH) by microsatellite analysis.    Results  We identified no evidence of bi-allelic tumor suppressor inactivation of  PRKN  or  FBXO4  via inactivating mutation or splice site perturbation, neither in combination with nor independent of LOH. Among the 82 cases, we encountered previously documented benign single nucleotide polymorphisms (SNPs) in 35 tumors at frequencies similar to those reported in the germlines of the general population. Eight cases exhibited intragenic LOH at the  PRKN  locus, in some cases extending to cover at least an additional 1.7 Mb of chromosome 6q25-26.  FBXO4  was not affected by LOH.    Conclusion:  The absence of evidence for specific bi-allelic inactivation in  PRKN  and  FBXO4  in this sizeable cohort suggests that these genes only rarely, if ever, serve as classic driver tumor suppressors responsible for the growth of PTAs.

Molecular analysis of cyclin D1 modulators PRKN and FBX4 as candidate tumor suppressors in sporadic parathyroid adenomas