Intragenic allelic loss and promoter hypermethylation of the RIZ1 tumor suppressor gene in parathyroid tumors and pheochromocytomas.
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.


METHODS
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.


CONCLUSIONS
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.
Carling
Tobias
T
Burnham Institute, La Jolla, CA, USA.
Du
Yong
Y
Fang
Wei
W
Correa
Pamela
P
Huang
Shi
S
D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000235:genetics; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D010282:Parathyroid Neoplasms / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D011495:Histone-Lysine N-Methyltransferase; C093563:PRDM2 protein, human