Ahomadegbe J C, Barrois M, Fogel S, Le Bihan M L, Douc-Rasy S, Duvillard P, Armand J P, Riou G
Laboratoire de Pharmacologie Clinique et Moléculaire, Institut Gustave Roussy, Villejuif, France.
Oncogene. 1995 Mar 16;10(6):1217-27.
We have analysed 78 head and neck carcinomas (50 node metastases and 28 primary tumors including 13 matched specimens) in 65 patients for p53 alterations. Mutations were found in 54 (69%) tumors. Of the 53 mutations within exons, 40 (76%) were missense, five (9%) nonsense and eight (15%) microdeletions or microinsertions. Twenty-five (47%) mutations were transitions mostly G-->A (40%) and 20 (38%) were transversions, mostly G-->T (25%), thus confirming the role of tobacco carcinogens in the induction of these mutations. The incidence of mutations was not different in primary tumors (68%) and node metastases (70%) indicating that this gene alteration was not related to the metastatic dissemination. For eight patients, mutations were observed in matched primary tumors and metastases, indicating clonal dissemination of tumor cells in most of these carcinomas. There was a good correlation between mutations and protein overexpression (Fisher's exact test P < 10(-4). Immunostaining was also observed in basal cells from normal epithelium and in early lesions adjacent to the primary tumor in 11/15 (73%) specimens irrespective of the presence of mutation in the corresponding tumors. These data confirm that p53 overexpression is an early event in the multistep process of epithelial cell carcinogenesis. Loss of heterozygosity for the TP53 locus was detected in 54% of tumors but no association was found with mutation (Fisher's exact test P = 0.14). No mdm-2 amplification was detected in any tumors. No correlation was found between mutation and clinical parameters, the 5-year survival rates were not different (log rank test P = 0.39) in patients with and without mutation. In conclusion, we have shown that p53 gene mutations and deletions and protein overexpression are frequent in the most aggressive head and neck carcinomas but are not associated with disease progression. The presence of protein in normal mucosa and in non-invasive lesions may constitute a biomarker for early stages of carcinogenesis.
我们分析了65例患者的78例头颈部癌（50例淋巴结转移癌和28例原发性肿瘤，包括13例配对标本）中的p53改变情况。在54例（69%）肿瘤中发现了突变。在外显子内的53个突变中，40个（76%）为错义突变，5个（9%）为无义突变，8个（15%）为微缺失或微插入。25个（47%）突变是转换，主要是G→A（40%），20个（38%）是颠换，主要是G→T（25%），从而证实了烟草致癌物在诱导这些突变中的作用。原发性肿瘤（68%）和淋巴结转移癌（70%）中的突变发生率没有差异，表明这种基因改变与转移扩散无关。对于8例患者，在配对的原发性肿瘤和转移癌中均观察到突变，表明在大多数这些癌中肿瘤细胞存在克隆性扩散。突变与蛋白过表达之间存在良好的相关性（Fisher精确检验P<10⁻⁴）。在11/15（73%）的标本中，无论相应肿瘤中是否存在突变，在正常上皮的基底细胞和原发性肿瘤相邻的早期病变中也观察到免疫染色。这些数据证实p53过表达是上皮细胞癌变多步骤过程中的早期事件。在54%的肿瘤中检测到TP53基因座的杂合性缺失，但未发现与突变相关（Fisher精确检验P = 0.14）。在任何肿瘤中均未检测到mdm - 2扩增。未发现突变与临床参数之间存在相关性，有突变和无突变患者的5年生存率没有差异（对数秩检验P = 0.39）。总之，我们已经表明p53基因突变、缺失和蛋白过表达在最具侵袭性的头颈部癌中很常见，但与疾病进展无关。正常黏膜和非侵袭性病变中蛋白的存在可能构成癌变早期阶段的生物标志物。
