Bates A S, Farrell W E, Bicknell E J, McNicol A M, Talbot A J, Broome J C, Perrett C W, Thakker R V, Clayton R N
Center for Cell and Molecular Medicine, University of Keele School of Postgraduate Medicine, Stoke-on Trent, United Kingdom.
J Clin Endocrinol Metab. 1997 Mar;82(3):818-24. doi: 10.1210/jcem.82.3.3799.
Tumors of the pituitary gland are usually benign adenomas and account for 10% of all intracranial neoplasms. Five pituitary tumors have previously been reported to harbor multiple allelic deletions. Of these, three displayed particularly aggressive biological behavior, whereas there were no clinical details provided for the others. This study was designed to test the hypothesis that genetic deletions are a marker of invasive behavior and to identify the loci most commonly involved. Accordingly, we studied two cohorts of pituitary tumors, classified radiologically 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 identified 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 allelic deletion, whereas 14 of 20 had more than 1. Of the 6 tumors with only 1 deletion, 5 involved the 11q13 locus, suggesting that this is an early change in the transition from noninvasive to invasive adenoma. Comparison of invasive and noninvasive tumors demonstrates a significantly higher frequency of deletions affecting 11q13 (P < 0.001), 13q12-14 (P < 0.05), and 10q26 (P < 0.05) in invasive tumors. In addition, allelic deletion correlates with increasingly invasive behavior (modified Hardy classification), as 73% of grade 4 tumors compared to 33% of grade 3 and 9.5% of grade 1 and 2 tumors demonstrated LOH at any locus. Furthermore, in some tumors we identified a breakpoint between markers intragenic and extragenic to the retinoblastoma gene (Rb1) on chromosome 13q, suggesting that tumor suppressor genes other than or in addition to Rb1 may be involved in pituitary tumorigenesis. This was further supported by the presence of Rb protein in two of four tumors where the genetic loss extended to include the intragenic marker D13S153. Early 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 possible using routine histological methods. A large prospective study is required in patients without radiological evidence of invasion to assess the value of LOH in predicting outcome and for planning treatment.
垂体肿瘤通常为良性腺瘤，占所有颅内肿瘤的10%。此前已有5例垂体肿瘤被报道存在多个等位基因缺失。其中，3例表现出特别侵袭性的生物学行为，而其他病例未提供临床细节。本研究旨在验证基因缺失是侵袭行为标志物这一假说，并确定最常受累的基因座。因此，我们研究了两组经放射学分类为侵袭性或非侵袭性的垂体肿瘤，以检测杂合性缺失（LOH）情况。与非侵袭性肿瘤（2.4%；P<0.001）相比，侵袭性肿瘤中LOH的频率显著更高（在所检测的所有基因座中占10.8%）。在研究的11个基因座中，侵袭性肿瘤中鉴定出的等位基因缺失有75%位于4个基因座：11q13、13q12 - 14、10q和1p。47例侵袭性肿瘤中有二十例有至少1个等位基因缺失的证据，而20例中有14例有不止1个缺失。在仅1个缺失的6例肿瘤中，5例涉及11q13基因座，提示这是从非侵袭性腺瘤向侵袭性腺瘤转变的早期变化。侵袭性和非侵袭性肿瘤的比较显示，侵袭性肿瘤中影响11q13（P<0.001）、13q12 - 14（P<0.05）和10q26（P<0.05）的缺失频率显著更高。此外，等位基因缺失与侵袭行为增加相关（改良的Hardy分类），因为4级肿瘤中有73%显示出任何基因座的LOH，而3级肿瘤为33%，1级和2级肿瘤为9.5%。此外，在一些肿瘤中，我们在13q染色体上视网膜母细胞瘤基因（Rb1）的基因内和基因外标记之间鉴定出一个断点，提示除Rb1之外或与之一起，其他肿瘤抑制基因可能参与垂体肿瘤发生。在4例基因缺失扩展至包括基因内标记D13S153的肿瘤中有2例存在Rb蛋白，这进一步支持了上述观点。通过基因分析（LOH）早期识别可能具有侵袭潜能的肿瘤，可能会提供有关潜在肿瘤行为的有用信息，并以常规组织学方法无法实现的方式辅助肿瘤管理。对于没有侵袭性放射学证据的患者，需要进行一项大型前瞻性研究，以评估LOH在预测预后和规划治疗方面的价值。
