FREQUENT LOSS OF HETEROZYGOSITY AT THE RETINOBLASTOMA SUSCEPTIBILITY GENE (RB) LOCUS IN AGGRESSIVE PITUITARY-TUMORS - EVIDENCE FOR A CHROMOSOME-13 TUMOR-SUPPRESSOR GENE OTHER THAN RB

Mice bearing retinoblastoma susceptibility gene (RE) germ-line mutations almost invariably develop pituitary neoplasms. We therefore tested 17 patients with pituitary tumors for loss of heterozygosity (LOH) using an RE sequence polymorphism and 5 polymorphic microsatellite markers surrounding the RE gene on the long arm of chromosome 13. In all of the 13 malignant or highly invasive pituitary tumor cases, and in 4 of their respective metastases, a RE allele was lost. In contrast, no LOH at the RE locus was detected in 4 benign pituitary adenoma cases. Three invasive tumors also lost a portion of 13q, which included D13s137, D13s133, and D13s118 telomeric and centromeric to RE, respectively. Immunohistochemical analysis, however, revealed the presence of RE protein in tumors with LOH and the RE locus. Therefore, although inactivation of RE may play a role in the development of invasive pituitary adenomas and carcinomas in mice, another tumor suppressor gene on 13q is likely involved in human pituitary tumor progression. LOH of 13q markers may also be of predictive value in determining the biological behavior of pituitary macroadenomas and their progression to invasiveness and frank malignancy.