Background: Loss of heterozygosity (LOH) at chromosome 1p is a common abnormality in both parathyroid tumors and pheochromocytomas. The recently characterized tumor suppressor gene RIZ1, located at 1p36, has emerged as a putative candidate to be involved in endocrine tumorigenesis.
Material: Presence of allelic loss, promoter hypermethylation, and mutational aberrations of the RIZ1 gene were investigated using PCR-based techniques in 47 parathyroid tumors and 23 pheochromocytomas. Gene expression studies used the RNAse protection assay.
Results: RIZ1 mRNA is expressed in pathologic tissues of the parathyroid and adrenal medulla. Thirteen of 47 (28%) parathyroid tumors, and 9/23 (39%) pheochromocytomas displayed LOH within the RIZ1 gene locus. Promoter hypermethylation of RIZ1 was detected in 36% of the parathyroid tumors and was related to LOH at the RIZ1 locus (P=.01), and absence of somatic mutation of the MEN1 gene (P=.044). In the pheochromocytomas, none of the benign tumors, but 2/4 malignant specimens exhibited RIZ1 promoter hypermethylation.
Conclusion: Alteration of the RIZ1 gene locus via intragenic allelic loss and promoter hypermethylation seem common in parathyroid tumors. Inactivation of the RIZ1 gene may cause parathyroid tumorigenesis via a mechanism in which genetic alteration of the MEN1 gene is redundant.