Hartmann A, Blaszyk H, McGovern R M, Schroeder J J, Cunningham J, De Vries E M, Kovach J S, Sommer S S
Department of Oncology, Mayo Clinic and Foundation, Rochester, Minnesota 55905.
Oncogene. 1995 Feb 16;10(4):681-8.
Most studies of mutations in the p53 tumor suppressor gene in tumors have examined only exons 5-8. Our laboratory previously found 64 mutations in exons 5-8 of the p53 gene in 194 primary breast cancers. Herein, we report 18 additional mutations found outside of exons 5-8. Mutations are present in exons 4, 9 and 10, and flanking splice junctions, but not in the promotor region or in exons 1, 2, 3 and 11. No missense mutations are found outside of exons 5-8. Instead, there is a predominance of frameshift mutations with lesser numbers of nonsense and splice site mutations. In contrast, the majority of mutations in exons 5-8 in this sample are missense changes and all of these are at amino acids that are identical in the 11 known p53 sequences that represent about 1.6 billion years of evolutionary divergence. The difference in mutational pattern between these two regions of the p53 gene is due to a lack of missense mutations and inframe microdeletions outside of exons 5-8. A review of our database of p53 mutations (De Vries et al., in preparation) shows that the patterns of mutation inside and outside of exons 5-8 differ in other types of cancers as well. The paucity of missense mutations in exons 2-4 and 9-11 in breast and other cancers (even at amino acids identical throughout p53 gene evolution) suggest that at least some missense mutations result in a phenotype other than malignant transformation. These data also illustrate the importance of examining identical exons when comparing the pattern of p53 gene mutations in different populations.
大多数关于肿瘤中p53肿瘤抑制基因的突变研究仅检测了外显子5至8。我们实验室先前在194例原发性乳腺癌中发现了p53基因外显子5至8中的64个突变。在此，我们报告在5至8号外显子之外又发现的18个突变。这些突变存在于外显子4、9和10以及侧翼剪接位点，但不存在于启动子区域或外显子1、2、3和11中。在5至8号外显子之外未发现错义突变。相反，移码突变占主导，无义突变和剪接位点突变数量较少。相比之下，该样本中外显子5至8中的大多数突变是错义变化，并且所有这些错义变化都发生在11个已知p53序列中相同的氨基酸位置，这些序列代表了约16亿年的进化分歧。p53基因这两个区域之间突变模式的差异是由于5至8号外显子之外缺乏错义突变和框内微缺失。对我们的p53突变数据库（De Vries等人，正在准备中）的回顾表明，5至8号外显子内外的突变模式在其他类型的癌症中也有所不同。乳腺癌和其他癌症中外显子2至4以及9至11中错义突变的缺乏（即使在p53基因进化过程中相同的氨基酸位置）表明，至少一些错义突变导致的表型不是恶性转化。这些数据还说明了在比较不同人群中p53基因突变模式时检查相同外显子的重要性。
