Detection of the first gross CDC73 germline deletion in an HPT‐JT syndrome family

Abstract

Hereditary primary hyperparathyroidism (HPT) may develop as a solitary endocrinopathy (FIHP) or as part of multiple endocrine neoplasia Type 1, multiple endocrine neoplasia Type 2A, or hereditary HPT-jaw tumor syndrome. Inactivating germline mutations of the tumor suppressor gene CDC73 account for 14 and 50% of all FIHP and HPT-JT patients, respectively, and have also been found in almost 20% of apparently sporadic parathyroid carcinoma patients. Although more than 60 independent germline mutations have been described, to date no rearrangement affecting the CDC73 locus has been identified. By means of multiplex-PCR we found a large germline deletion affecting the whole gene in a two-generation HPT-JT family. Subsequently array-CGH and specific PCR analysis determined that the mutation spanned ∼ 547 kb, and included four additional genes: TROVE2, GLRX2, B3GALT2, and UCHL5. Although no clear mutation-specific phenotype was found associated to the presence of the mutation, further studies are needed to assess whether the loss of the neighboring genes could modify the phenotype of carriers. There was complete absence of nuclear staining in the two HPT-JT-related tumors available. The finding of the first rearrangement affecting the CDC73 gene warrants screening for this tumor suppressor gene inactivation mechanism not only in high-risk CDC73 point mutation-negative HPT-JT families, but also in FIHP patients.

Cdc73 Subunit of Paf1 Complex Contains C-terminal Ras-like Domain That Promotes Association of Paf1 Complex with Chromatin

“…The gene encoding parafibromin/hCdc73 has long been recognized as a tumor suppressor gene in humans. Inactivating germ line mutations account for ϳ50% of patients with hyperparathyroidism-jaw tumor syndrome (HPT-JT) (41) and are associated with a variety of related cancers, including parathyroid carcinomas and ossifying fibromas (42,43). Interestingly, parafibromin can function as a tumor suppressor by recruiting histone methyltransferases to inhibit cyclin D1 expression (44,45) and as an oncogenic factor by activating Wnt signaling (46).…”

Parathyroid Cancer and the CDC73 Tumor Suppressor Gene

“…Most such CDC73 mutations are predicted to cause loss-of-function via frameshift or nonsense mutations [40]. Patients with germline deletion of the CDC73 gene have also been reported [41][42][43].…”

Parathyroid carcinoma

“…Among studies using the most stringent diagnostic criteria for parathyroid cancer, namely extracapsular invasion and/or distant metastasis, the mutation frequency is 77% [13][14][15] . In addition to intragenic mutations, gross deletions of CDC73 have also been reported [17][18][19] . Biallelic inactivation of CDC73 can be demonstrated in many parathyroid cancers [13][14][15] .…”