Frebourg T, Malkin D, Friend S
MGH Cancer Center, Charleston, Massachusetts 02129.
Princess Takamatsu Symp. 1991;22:61-70.
It has been well established that sometimes cancer clusters within specific families. This has suggested the possibility that some of those families might carry genetic defects which provide susceptibility to specific cancers. Retinoblastoma, an embryonal tumor of the eye represents an extreme example of a tumor which has a dramatic genetic component. Several studies have shown that inactivation at the retinoblastoma gene is probably both necessary and sufficient to initiate retinoblastoma formation. Patients who survive the inherited form of the disease are at risk of developing mesenchymal tumors, melanoma and brain tumors in as high as 10% of the patients before they are 40 years old. Because the product of the retinoblastoma gene, p105Rb, is expressed in all cell types, the obvious question is what accounts for these tissue specific differences in the role of p105Rb. Small cell lung carcinomas virtually all have associated mutations in the Rb gene and yet those tumors do not occur at a significantly increased frequency in patients with the hereditary form of retinoblastoma. In order to identify genes which might predispose to some of the more common adult malignancies, we have focused on one form of hereditary breast cancer. We chose a rare form of hereditary breast cancer which occurs in families with sarcomas (Li-Fraumeni Syndrome). By use of the candidate gene approach we tested which germ line p53 mutations were found in affected family members with Li-Fraumeni Syndrome (LFS). We have found that virtually all of the families with LFS have germ line p53 mutations, and that these tumors have undergone inactivation of the remaining wild-type p53 allele. In order to investigate the role of germ line p53 mutations outside of these rare families, we have begun to investigate other high risk groups. These results indicate that de novo germ line p53 mutations certainly occur in these high risk groups. These findings along with the recognition of the germ line p53 mutations in families with LFS provide clues about the importance of uncovering hidden susceptibilities from germ line tumor suppressor genes not only for the care of patients, but also for understanding the primary events that normally regulate the growth of cells in various tissue.
癌症有时会在特定家族中聚集，这一点已经得到充分证实。这表明这些家族中的一些可能携带导致易患特定癌症的基因缺陷。视网膜母细胞瘤是一种眼部胚胎性肿瘤，是具有显著遗传成分的肿瘤的极端例子。多项研究表明，视网膜母细胞瘤基因的失活可能是引发视网膜母细胞瘤形成的必要且充分条件。患有遗传性视网膜母细胞瘤的幸存者在40岁之前患间充质肿瘤、黑色素瘤和脑肿瘤的风险高达10%。由于视网膜母细胞瘤基因的产物p105Rb在所有细胞类型中都有表达，一个明显的问题是，p105Rb作用中这些组织特异性差异的原因是什么。小细胞肺癌几乎都有Rb基因相关突变，但遗传性视网膜母细胞瘤患者中这些肿瘤并未显著增加。为了确定可能导致一些更常见成人恶性肿瘤的基因，我们聚焦于一种遗传性乳腺癌。我们选择了一种罕见的遗传性乳腺癌，它发生在患有肉瘤的家族中（李-弗劳梅尼综合征）。通过候选基因方法，我们检测了患有李-弗劳梅尼综合征（LFS）的受影响家庭成员中发现了哪些种系p53突变。我们发现，几乎所有LFS家族都有种系p53突变，并且这些肿瘤的剩余野生型p53等位基因也已失活。为了研究这些罕见家族之外种系p53突变的作用，我们开始研究其他高危人群。这些结果表明，新生种系p53突变肯定会在这些高危人群中发生。这些发现以及对LFS家族种系p53突变的认识，不仅为患者护理，也为理解正常调节各种组织中细胞生长的主要事件，提供了有关从种系肿瘤抑制基因中发现隐藏易感性重要性的线索。
