Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene.
Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene.
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发表时间：
1991-05
影响因子：
9.8
通讯作者：
T. Sakai;J. Toguchida;N. Ohtani;D. Yandell;J. Rapaport;T. Dryja
中科院分区：
文献类型：
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作者：
T. Sakai;J. Toguchida;N. Ohtani;D. Yandell;J. Rapaport;T. Dryja
视网膜母细胞瘤基因的失活似乎在视网膜母细胞瘤、骨肉瘤和其他恶性肿瘤的发生中具有重要作用。该基因通常由于功能丧失突变而失活，尽管表观遗传现象（例如启动子区域的超甲基化）可能具有相同的效果。我们研究了从 56 个原发性视网膜母细胞瘤中纯化的 DNA 中视网膜母细胞瘤基因 5' 端的甲基化模式，包括其启动子区域和外显子 1。我们发现了五个具有高甲基化证据的肿瘤，全部来自单侧单发患者。从这些患者的白细胞中纯化的 DNA 中未检测到甲基化异常。有趣的是，在其中一种肿瘤中，高甲基化仅限于一个等位基因。 1,306 bp 的序列中没有突变，包括可能导致等位基因特异性高甲基化的高甲基化区域。我们相信，我们在这些肿瘤中发现的视网膜母细胞瘤基因的高甲基化对应于该基因的等位基因失活，并且我们推测，不改变核苷酸序列的错误的高甲基化偶尔在这种癌症的发生中发挥作用。如果这是真的，那么具有高甲基化的视网膜母细胞瘤可能可以用干扰 DNA 甲基化的化疗药物来治疗。
Inactivation of the retinoblastoma gene appears to have a fundamental role in the genesis of retinoblastoma, osteosarcoma, and other malignant tumors. The gene is generally inactivated because of loss-of-function mutations, although epigenetic phenomena, such as hypermethylation of the promoter region, could possibly have the same effect. We investigated the methylation pattern at the 5' end of the retinoblastoma gene, including its promoter region and exon 1, in DNA purified from 56 primary retinoblastomas. We found five tumors with evidence for hypermethylation, all from unilateral, simplex patients. No methylation abnormalities were detected in DNA purified from the leukocytes from these patients. It is interesting that in one of these tumors the hypermethylation was confined to one allele. There were no mutations in a 1,306-bp sequence including the hypermethylated region that might account for the allele-specific hypermethylation. We believe that the hypermethylation of the retinoblastoma gene that we found in these tumors corresponds to the allelic inactivation of the gene, and we speculate that erroneous hypermethylation without alteration of nucleotide sequence occasionally plays a role in the genesis of this cancer. If this is true, then retinoblastomas with hypermethylation might be treatable with chemotherapeutic agents that interfere with methylation of DNA.