CHROMOSOME-17 DELETIONS AND P53 GENE-MUTATIONS IN COLORECTAL CARCINOMAS
CHROMOSOME-17 DELETIONS AND P53 GENE-MUTATIONS IN COLORECTAL CARCINOMAS
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DOI：
10.1126/science.2649981
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发表时间：
1989-04-14
期刊：
影响因子：
56.9
通讯作者：
VOGELSTEIN, B
中科院分区：
文献类型：
--
作者：
BAKER, SJ;FEARON, ER;VOGELSTEIN, B
先前的研究表明，超过75%的结直肠癌会发生17号染色体短臂的等位基因缺失。20个染色体17p标记被用来定位这些肿瘤中常见的缺失区，该区域包含17p12至17p13.3条带。这个区域含有转化相关蛋白P53的基因。Southern和Northern杂交实验没有提供p53基因或周围序列发生明显变化的证据。为了更严格地检验p53是缺失的目标的可能性，分析了两个肿瘤的p53编码区；这两个肿瘤，像大多数结直肠癌一样，存在染色体17p的等位基因缺失，并从剩余的等位基因中表达了相当数量的P53信使RNA。其余p53等位基因在两个肿瘤中均发生突变，其中一个肿瘤的第143位密码子上的丙氨酸取代了缬氨酸，第二个肿瘤的第175位密码子上的组氨酸取代了精氨酸。这两种突变都发生在p53基因的一个高度保守的区域，此前在小鼠p53癌基因中发现了该区域的突变。这些数据表明，P53基因突变可能与大肠肿瘤有关，可能是通过野生型P53基因的肿瘤抑制功能失活。
Previous studies have demonstrated that allelic deletions of the short arm of chromosome 17 occur in over 75% of colorectal carcinomas. Twenty chromosome 17p markers were used to localize the common region of deletion in these tumors to a region contained with bands 17p12 to 17p13.3. This region contains the gene for the transformation-associated protein p53. Southern and Northern blot hybridization experiments provided no evidence for gross alterations of the p53 gene or surrounding sequences. As a more rigorous test of the possibility that p53 was a target of the deletions, the p53 coding regions from two tumors were analyzed; these two tumors, like most colorectal carcinomas, had allelic deletions of chromosome 17p and expressed considerable amounts of p53 messenger RNA from the remaining allele. The remaining p53 allele was mutated in both tumors, with an alanine substituted for valine at codon 143 of one tumor and a histidine substituted for arginine at codon 175 of the second tumor. Both mutations occurred in a highly conserved region of the p53 gene that was previously found to be mutated in murine p53 oncogenes. The data suggest that p53 gene mutations may be involved in colorectal neoplasia, perhaps through inactivation of a tumor suppressor function of the wild-type p53 gene.