ALLELIC DELETION IN PITUITARY-ADENOMAS REFLECTS AGGRESSIVE BIOLOGICAL-ACTIVITY AND HAS POTENTIAL VALUE AS A PROGNOSTIC MARKER

Tumors of the pituitary gland are usually benign adenomas and account for 10% of all intracranial neoplasms. Five pituitary tumors have prev iously been reported to harbor multiple allelic deletions. Of these, t hree displayed particularly aggressive biological behavior, whereas th ere were no clinical details provided for the others. This study was d esigned to test the hypothesis that genetic deletions are a marker of invasive behavior and to identify the loci most commonly involved. Acc ordingly, we studied two cohorts of pituitary tumors, classified radio logically as invasive or noninvasive, for loss of heterozygosity (LOH) . There is a significantly higher frequency of LOH in invasive tumors (10.8% of all loci examined) compared to noninvasive tumors (2.4%; P < 0.001). Of the 11 loci investigated, 75% of the allelic deletions ide ntified in invasive tumors were found at 4 loci: 11q13, 13q12-14, 10q, and 1p. Twenty of 47 invasive tumors had evidence of at least 1 allel ic deletion, whereas 14 of 20 had more than 1. Of the 6 tumors with on ly 1 deletion, 5 involved the 11q13 locus, suggesting that this is an early change in the transition from noninvasive to invasive adenoma. C omparison of invasive and noninvasive tumors demonstrates a significan tly higher frequency of deletions affecting 11q13 (P < 0.001), 13q12-1 4 (P < 0.05), and 10q26 (P < 0.05) in invasive tumors. In addition, al lelic deletion correlates with increasingly invasive behavior (modifie d Hardy classification), as 73% of grade 4 tumors compared to 33% of g rade 3 and 9.5% of grade 1 and 2 tumors demonstrated LOH at any locus. Furthermore, in some tumors we identified a breakpoint between marker s intragenic and extragenic to the retinoblastoma gene (Rb1) on chromo some 13q, suggesting that tumor suppressor genes other than or in addi tion to Rbl may be involved in pituitary tumorigenesis. This was furth er supported by the presence of Rb protein in two of four tumors where the genetic loss extended to include the intragenic marker D13S153. E arly identification of tumors with likely invasive potential by means of genetic analysis (LOH) may provide useful information on potential tumor behavior and aid tumor management in a manner that is not possib le using routine histological methods. A large prospective study is re quired in patients without radiological evidence of invasion to assess the Value of LOH in predicting outcome and for planning treatment.