Abstract 5646: Germline activating mutations in the proto-oncogene GCM2 in primary hyperparathyroidism

Abstract

Abstract Primary hyperparathyroidism (PHPT) is a common endocrine disease caused by parathyroid tumors (adenoma or hyperplasia). The hypersecreting parathyroid tumor elevates serum parathyroid hormone level, which causes hypercalcemia and the classical symptoms of PHPT, including kidney stones, osteoporosis, and neuromuscular symptoms associated with hypercalcemia, such as muscle weakness, drowsiness, and depression. Familial PHPT occurs in an isolated nonsyndromal form, termed familial isolated hyperparathyroidism (FIHP), or as part of a syndrome, such as multiple endocrine neoplasia type 1 or hyperparathyroidism-jaw tumor syndrome. We performed exome sequencing on germline DNA of eight index cases from eight unrelated kindreds with FIHP. Rare variants were identified (minor allele frequency <1%), and selected variants were assessed for co-segregation in affected family members by Sanger sequencing. Candidate genes were then screened in an additional 32 kindreds with FIHP. The functional consequence of variants in one FIHP candidate gene (GCM2, a parathyroid tissue-specific transcription factor) was analyzed in a cell culture model. In eight kindreds with FIHP, we identified three rare GCM2 missense variants. Functional characterization of GCM2 variants and deletion-analyses revealed a small C-terminal Conserved Inhibitory Domain (CCID). Two of the three rare variants were recurrent, located in the CCID that enhanced the transcriptional activity of GCM2, and found in seven of 40 (18%) kindreds with FIHP. Functional assays for transcriptional activity demonstrated that these two rare variants acted as gain-of-function mutations, suggesting that GCM2 is a parathyroid proto-oncogene. We further investigated the ethnicity of individuals with GCM2 CCID activating variants in PHPT patient samples and in genome survey datasets. Our results demonstrate that germline activating mutations in the GCM2 CCID can cause FIHP, and specific activating mutations expose a large population at risk for PHPT. Our findings of the first gene with mutations specific for FIHP are expected to have an important impact on clinical practice, including treatment decisions and genetic testing of individuals with PHPT and family members. Citation Format: Bin Guan, James M. Welch, Julie C. Sapp, Hua Ling, Meghana Vemulapalli, Yulong Li, Jennifer J. Johnston, Electron Kebebew, Leslie G. Biesecker, William F. Simonds, Stephen J. Marx, Sunita K. Agarwal. Germline activating mutations in the proto-oncogene GCM2 in primary hyperparathyroidism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5646. doi:10.1158/1538-7445.AM2017-5646