Ectopic Production of Parathyroid Hormone in a Patient with Sporadic Medullary Thyroid Cancer

Elevation of serum parathyroid hormone (PTH) in patients with medullary thyroid cancer (MTC) is usually found in multiple endocrine neoplasia type 2A (MEN2A). However, ectopic production of PTH is rare and its molecular etiology remains largely uninvestigated. We report a case of ectopic production of PTH by a sporadic MTC. The etiology of ectopic PTH gene expression was examined, focusing on GCM2 which has a crucial role in developing parathyroid glands. We observed ectopic expression of the PTH and GCM2 genes in tissues from the tumor and metastatic lymph nodes. However, GCM2 gene expression was also detected in adjacent thyroid tissue and lymphoblasts, in which PTH gene expression was absent. Hypomethylation of the PTH promoter, which is reportedly associated with ectopic production of PTH, was not seen in either the tumor tissue or metastatic lymph nodes. Meanwhile, DNA hypomethylation was seen in a CpG island identified in the GCM2 promoter region, regardless of whether or not the GCM2 gene was expressed. We showed that transcriptional activity of the CpG island sequences cloned into a reporter plasmid was dependent upon DNA methylation. Finally, we present the first report of a PTH-producing MTC. There was no apparent association between ectopic PTH and GCM2 gene expression, despite co-expression of the two genes. Neither genomic rearrangement nor DNA hypomethylation in the PTH gene appeared responsible for ectopic production of PTH. Although DNA hypomethylation may be necessary for the GCM2 gene expression, ectopic expression of GCM2 won’t be possible by DNA hypomethylation alone.