Goodrich D W, Lee W H
Department of Pathology, School of Medicine, University of California at San Diego, La Jolla 92093.
Cancer Surv. 1990;9(3):529-54.
Retinoblastoma is a potentially hereditary cancer. Refinement of the genetic and epidemiological analysis of the disease has uncovered two distinct classes of retinoblastoma. Sporadic retinoblastoma is generally unilateral and unifocal, and is diagnosed at the late age of about two years. A few of these sporadic cases are probably due to a germ cell mutation inherited from a parent and hence can be classified as hereditary. Familial retinoblastoma is generally diagnosed at an earlier age, at 11 months, and is typically bilateral and/or multifocal. These observations have been incorporated into a 'two hit' mutational inactivation hypothesis of the origin of retinoblastoma. The molecular cloning and characterization of a candidate retinoblastoma susceptibility gene and its gene product has allowed a critical testing of this hypothesis. All of the predications of the model have been confirmed by experiment. These include inheritance of one mutated retinoblastoma susceptibility (RB) allele as the origin of hereditary retinoblastoma, subsequent loss of the remaining allele upon the genesis of the tumour, the involvement of the same RB gene in both sporadic and hereditary retinoblastoma, the somatic mutation of both RB alleles in sporadic retinoblastoma, the lack of evidence for expression of a normal RB gene product in any retinoblastoma yet examined, the inactivational nature of RB mutations and the recessiveness of these mutated alleles. The RB gene also exhibits suppression of neoplastic properties when introduced into retinoblastoma cells and also into some other tumour cells. These results mutually reinforce the two hit inactivation hypothesis as well as the cloned gene's correct identification as the retinoblastoma susceptibility locus. The confirmation of this hypothesis is, therefore, nearing completion. The definitive proof is achievable with the advent of chimeric mouse technology, which will allow construction of mice with one or both RB alleles that have been inactivated by mutation. Analysis of such mice may allow us to determine if inactivation of both RB alleles is necessary and sufficient for the development of retinoblastoma and possibly other tumour types. The molecular isolation of the RB gene is an important achievement in research on cancer. For the first time, it has become possible to examine, at the molecular level, genes which suppress the tumorigenicity of cancer cells. Analysis of such cloned genes should yield insight into mechanisms of oncogenesis, gene regulation and cellular differentiation complementary to the knowledge which has long been accumulating from the study of oncogenes.
视网膜母细胞瘤是一种具有潜在遗传性的癌症。对该疾病的基因和流行病学分析的细化揭示了两种不同类型的视网膜母细胞瘤。散发性视网膜母细胞瘤通常为单侧且单灶性，在约两岁的较晚年龄被诊断出来。其中一些散发性病例可能是由于从父母遗传而来的生殖细胞突变，因此可归类为遗传性。家族性视网膜母细胞瘤通常在11个月的较早年龄被诊断出来，通常为双侧和/或多灶性。这些观察结果已被纳入视网膜母细胞瘤起源的“两次打击”突变失活假说。一个候选视网膜母细胞瘤易感基因及其基因产物的分子克隆和表征使得对该假说进行关键测试成为可能。该模型的所有预测都已通过实验得到证实。这些包括作为遗传性视网膜母细胞瘤起源的一个突变的视网膜母细胞瘤易感（RB）等位基因的遗传，肿瘤发生时剩余等位基因的随后丢失，同一RB基因在散发性和遗传性视网膜母细胞瘤中的参与，散发性视网膜母细胞瘤中两个RB等位基因的体细胞突变，在任何已检测的视网膜母细胞瘤中均缺乏正常RB基因产物表达的证据，RB突变的失活性质以及这些突变等位基因的隐性。当将RB基因导入视网膜母细胞瘤细胞以及一些其他肿瘤细胞时，它还表现出对肿瘤特性的抑制作用。这些结果相互强化了两次打击失活假说以及克隆基因作为视网膜母细胞瘤易感位点的正确鉴定。因此，对该假说的证实已接近完成。随着嵌合小鼠技术的出现，最终的证据是可以实现的，这将允许构建具有一个或两个已通过突变失活的RB等位基因的小鼠。对这类小鼠的分析可能使我们能够确定两个RB等位基因的失活对于视网膜母细胞瘤以及可能其他肿瘤类型的发展是否必要和充分。RB基因的分子分离是癌症研究中的一项重要成就。首次有可能在分子水平上研究抑制癌细胞致瘤性的基因。对这类克隆基因的分析应该能够深入了解肿瘤发生、基因调控和细胞分化的机制，这与长期以来从癌基因研究中积累的知识相辅相成。
