Casey G, Lopez M E, Ramos J C, Plummer S J, Arboleda M J, Shaughnessy M, Karlan B, Slamon D J
Department of Cancer Biology, The Cleveland Clinic Research Institute, Ohio 44195, USA.
Oncogene. 1996 Nov 7;13(9):1971-81.
p53 mutations are the most common genetic alterations found in human malignancies. However current estimates of p53 alterations in cancers may be inaccurate because there is evidence that current approaches do not detect all p53 alterations. In this study we determine the status of the p53 gene by complete DNA sequencing of exons 2 through 11 as well as immunohistochemical staining in cohorts of primary human breast, ovarian and non small cell lung cancer. Overall, 24 of 93 (26%) breast cancers, 62 of 108 (57%) ovarian cancers and 88 of 154 (57%) non small cell lung cancers contained DNA sequence mutations, whereas positive immunohistochemical staining was detected in 15 of 64 (23%) breast, 35 of 94 (37%) ovarian, and 63 of 137 (46%) lung cancers. Of those tumors that contained mutations, the mutation occurred outside the 'hot-spot' region in 19% of breast, 18% of ovarian and 17% of lung tumors, indicating that a substantial number of mutations remain undetected in studies that are restricted to exons 5 through 9. We observed a high concordance between the presence of p53 missense mutations and positive immunohistochemical staining, but a poor concordance between other types of mutations and staining in all three types of malignancies. We conclude that a combination of DNA sequence analysis of exons 2 through 11 and immunohistochemical staining are required to detect all known alterations in the p53 gene in human malignancies.
p53突变是人类恶性肿瘤中最常见的基因改变。然而，目前对癌症中p53改变的估计可能不准确，因为有证据表明当前方法无法检测到所有的p53改变。在本研究中，我们通过对2至11号外显子进行完整DNA测序以及对原发性人类乳腺癌、卵巢癌和非小细胞肺癌队列进行免疫组化染色来确定p53基因的状态。总体而言，93例乳腺癌中有24例（26%）、108例卵巢癌中有62例（57%）以及154例非小细胞肺癌中有88例（57%）存在DNA序列突变，而在64例乳腺癌中有15例（23%）、94例卵巢癌中有35例（37%）以及137例肺癌中有63例（46%）检测到免疫组化染色呈阳性。在那些含有突变的肿瘤中，19%的乳腺癌、18%的卵巢癌和17%的肺癌中突变发生在“热点”区域之外，这表明在仅限于5至9号外显子的研究中，大量突变仍未被检测到。我们观察到p53错义突变的存在与免疫组化染色阳性之间具有高度一致性，但在所有三种类型的恶性肿瘤中，其他类型的突变与染色之间的一致性较差。我们得出结论，需要结合对2至11号外显子的DNA序列分析和免疫组化染色来检测人类恶性肿瘤中p53基因的所有已知改变。
