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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 RB¹

Department of Medicine, Cedars-Sinai Research Institute-University of California Los Angeles School of Medicine, Los Angeles, California 90048 [L. P., S. M., D. P.]; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905 [B. S.]; Department of Pathology, St. Michael's Hospital, University of Toronto, Toronto, Ontario M5B 1W8, Canada [K. K.]; and Center for Biotechnology, Baylor College of Medicine, The Woodlands, Texas 77381 [W. F. B.]

Mice bearing retinoblastoma susceptibility gene (RB) germ-line mutations almost invariably develop pituitary neoplasms. We therefore tested 17 patients with pituitary tumors for loss of heterozygosity (LOH) using an RB sequence polymorphism and 5 polymorphic microsatellite markers surrounding the RB 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 RB allele was lost. In contrast, no LOH at the RB 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 RB, respectively. Immunohistochemical analysis, however, revealed the presence of RB protein in tumors with LOH and the RB locus. Therefore, although inactivation of RB 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.

¹ Supported by NIH Grants DK42792 (S. M.), DK02023 (D. P.), DK T-32 DK07682, and CA-54672 (W. B.).

² To whom requests for reprints should be addressed, at Division of Endocrinology, B131, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048.

Received 1/ 9/95. Accepted 3/ 3/95.

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