MOLECULAR-GENETIC ANALYSIS OF THE MECHANISM OF TUMORIGENESIS IN ACOUSTIC NEUROMA

Objective: Acoustic neuroma, both familial and sporadic, is clinically and biologically a heterogeneous condition with a wide variation in a ge of presentation, length of history, and tumor growth rate. In an at tempt to correlate this clinical diversity with the underlying molecul ar pathology, we have analyzed 43 paired blood-tumor DNA samples from patients with acoustic neuromas. Design: Molecular genetic analysis. S etting: Molecular genetic research laboratory. Patients: Paired blood- tumor DNA samples were obtained from 43 patients (41 sporadic and two patients with neurofibromatosis type 2). Main Outcome Measures: Loss o f constitutional heterozygosity was looked for in the region of tumor suppressor genes on chromosomes 3p, 5q, 11p, 17p, 17q, and 22. Results : We found loss of heterozygosity exclusively for markers on chromosom e 22. Thirty-nine percent of tumors showed allele loss, and in each ca se the loss of heterozygosity included the region of the neurofibromat osis type 2 (NF2) gene. No loss of heterozygosity was detected in the region of known or putative suppressor genes in chromosomes 3p, 5q, 11 p, 17p, and 17q. Conclusions: This study has demonstrated that (1) chr omosome 22 allele loss is a frequent event in sporadic acoustic neurom a; (2) the minimal region of loss of heterozygosity in acoustic neurom a includes the NF2 gene; (3) the known tumor suppressor genes investig ated (VHL, adenomatous polyposis coli, WT2, p53, and NF1) do not appea r to be important in the pathogenesis of acoustic neuroma; and (4) pat ients with extensive chromosome 22 loss tended to be younger and with a slightly shorter clinical history than those with no detectable alle le loss.