Eisenberg M B, Woloschak M, Sen C, Wolfe D
Department of Neurosurgery, Mount Sinai School of Medicine, New York, NY, USA.
Surg Neurol. 1997 Feb;47(2):156-60; discussion 160-1. doi: 10.1016/s0090-3019(96)00432-6.
The retinoblastoma (Rb) gene is a well characterized tumor suppressor gene in which loss of heterozygosity has been implicated in a number of malignancies including osteosarcoma and breast carcinoma. Chordomas and chondrosarcomas are rare skull base neoplasms with a propensity for local recurrences, resistance to conventional radiotherapy, and a 5%-30% incidence of metastases. Except for the so called "chondroid chordoma," histologic features do not correlate with the clinical behavior or growth patterns of these tumors. No study to date has investigated what role tumor suppressor genes or oncogenes play in the development and continued growth of these rare neoplasms.
In order to evaluate the role of the retinoblastoma tumor suppressor gene in chordomas and chondrosarcomas we screened seven chordomas and two chondrosarcomas located at the skull base for loss of heterozygosity (LOH) of the Rb gene. Genomic DNA was extracted from tumor specimens as well as matched control tissue and utilizing a polymerase chain reaction technique, intron 17 and 20 were amplified from each specimen. The intron 17 product was then digested with the restriction endonuclease X ba1 followed by electrophoresis on a 1% agrose gel. The intron 20 amplified products were electrophoresed on a nondenaturing 6% polyacrylamide gel.
We demonstrated LOH at intron 17 of the retinoblastoma gene in 2/7 chordomas and in 0/2 chondrosarcomas. The two chordomas possessing LOH were particularly aggressive tumors demonstrating extensive involvement of the skull base and rapid recurrences following radical resections.
Alterations of the Rb gene may play a role in the growth of skull base chordomas with LOH of the Rb gene serving as a marker for more aggressive tumors. This report represents the first study evaluating the Rb gene in chordomas or chondrosarcomas and is the first report of allelic loss of the Rb gene in skull base chordomas.
视网膜母细胞瘤（Rb）基因是一种特征明确的肿瘤抑制基因，杂合性缺失与包括骨肉瘤和乳腺癌在内的多种恶性肿瘤有关。脊索瘤和软骨肉瘤是罕见的颅底肿瘤，容易局部复发，对传统放疗有抗性，转移发生率为5% - 30%。除了所谓的“软骨样脊索瘤”，组织学特征与这些肿瘤的临床行为或生长模式并无关联。迄今为止，尚无研究调查肿瘤抑制基因或癌基因在这些罕见肿瘤的发生和持续生长中所起的作用。
为了评估视网膜母细胞瘤肿瘤抑制基因在脊索瘤和软骨肉瘤中的作用，我们筛查了位于颅底的7例脊索瘤和2例软骨肉瘤，检测Rb基因的杂合性缺失（LOH）。从肿瘤标本以及匹配的对照组织中提取基因组DNA，利用聚合酶链反应技术，从每个标本中扩增内含子17和20。然后用限制性内切酶Xba1消化内含子17产物，随后在1%琼脂糖凝胶上进行电泳。内含子20扩增产物在非变性6%聚丙烯酰胺凝胶上进行电泳。
我们在2/7的脊索瘤中检测到视网膜母细胞瘤基因内含子17存在LOH，而在0/2的软骨肉瘤中未检测到。这两例存在LOH的脊索瘤是特别侵袭性的肿瘤，显示出颅底广泛受累，根治性切除后迅速复发。
Rb基因的改变可能在颅底脊索瘤的生长中起作用，Rb基因的LOH可作为更具侵袭性肿瘤的标志物。本报告是第一项评估脊索瘤或软骨肉瘤中Rb基因的研究，也是颅底脊索瘤中Rb基因等位基因缺失的首次报告。
