Yandell D W, Campbell T A, Dayton S H, Petersen R, Walton D, Little J B, McConkie-Rosell A, Buckley E G, Dryja T P
Department of Ophthalmology, Harvard Medical School, Boston, MA.
N Engl J Med. 1989 Dec 21;321(25):1689-95. doi: 10.1056/NEJM198912213212501.
Mutations of the retinoblastoma gene, most of which cannot be detected by conventional Southern blotting, are known to cause both the nonhereditary and hereditary forms of retinoblastoma and have been implicated in the development of other cancers. Nonhereditary retinoblastoma is caused by a somatic mutation. Hereditary retinoblastoma is caused by a germ-cell mutation, most often a new one, and thus there is usually no family history of the disease. Unlike patients with the nonhereditary disease, those with the hereditary form are at risk for additional retinoblastomas, and their progeny are at risk for the tumors. We used a sensitive technique of primer-directed enzymatic amplification, followed by DNA sequence analysis, to identify mutations as small as a single nucleotide change in tumors from seven patients with simplex retinoblastoma (with no family history of the disease). In four patients the mutation involved only the tumor cells, and in three it involved normal somatic cells as well as tumor cells but was not found in either parent; thus, these mutations appeared to be new, germ-cell mutations. In addition, we found point mutations in cells from a bladder carcinoma, a small-cell carcinoma of the lung, and another retinoblastoma. We conclude that the technique that we have described can distinguish hereditary from nonhereditary retinoblastoma and that it is useful in risk estimation and genetic counseling.
视网膜母细胞瘤基因的突变，其中大多数无法通过传统的Southern印迹法检测到，已知会导致视网膜母细胞瘤的非遗传性和遗传性形式，并与其他癌症的发生有关。非遗传性视网膜母细胞瘤由体细胞突变引起。遗传性视网膜母细胞瘤由生殖细胞突变引起，最常见的是新发生的突变，因此通常没有该疾病的家族史。与非遗传性疾病患者不同，遗传性视网膜母细胞瘤患者有发生额外视网膜母细胞瘤的风险，其后代也有患肿瘤的风险。我们使用了一种敏感的引物定向酶促扩增技术，随后进行DNA序列分析，以识别来自7例单纯性视网膜母细胞瘤（无该疾病家族史）患者肿瘤中仅单个核苷酸变化这样小的突变。在4例患者中，突变仅涉及肿瘤细胞，在3例患者中，突变不仅涉及肿瘤细胞还涉及正常体细胞，但在父母双方中均未发现；因此，这些突变似乎是新的生殖细胞突变。此外，我们在来自一例膀胱癌、一例肺小细胞癌和另一例视网膜母细胞瘤的细胞中发现了点突变。我们得出结论，我们所描述的技术可以区分遗传性和非遗传性视网膜母细胞瘤，并且在风险评估和遗传咨询中很有用。
