Poeta M Luana, Manola Judith, Goldwasser Meredith A, Forastiere Arlene, Benoit Nicole, Califano Joseph A, Ridge John A, Goodwin Jarrard, Kenady Daniel, Saunders John, Westra William, Sidransky David, Koch Wayne M
Johns Hopkins University, Baltimore, MD 21287, USA.
N Engl J Med. 2007 Dec 20;357(25):2552-61. doi: 10.1056/NEJMoa073770.
The abrogation of function of the tumor-suppressor protein p53 as a result of mutation of its gene, TP53, is one of the most common genetic alterations in cancer cells. We evaluated TP53 mutations and survival in patients with squamous-cell carcinoma of the head and neck.
A total of 560 patients with squamous-cell carcinoma of the head and neck who were treated surgically with curative intent were enrolled in our prospective multicenter, 7-year study. TP53 mutations were analyzed in DNA from the tumor specimens with the use of the Affymetrix p53 chip and the Surveyor DNA endonuclease and denaturing high-performance liquid chromatography. Mutations were classified into two groups, disruptive and nondisruptive, according to the degree of disturbance of protein structure predicted from the crystal structure of the p53-DNA complexes. TP53 mutational status was compared with clinical outcome.
TP53 mutations were found in tumors from 224 of 420 patients (53.3%). As compared with wild-type TP53, the presence of any TP53 mutation was associated with decreased overall survival (hazard ratio for death, 1.4; 95% confidence interval [CI], 1.1 to 1.8; P=0.009), with an even stronger association with disruptive mutations (hazard ratio, 1.7; 95% CI, 1.3 to 2.4; P<0.001) and no significant association with nondisruptive mutations (hazard ratio, 1.2; 95% CI, 0.9 to 1.7; P=0.16). In multivariate analyses a disruptive TP53 alteration, as compared with the absence of a TP53 mutation, had an independent, significant association with decreased survival (hazard ratio, 1.7; 95% CI, 1.2 to 2.4; P=0.003).
Disruptive TP53 mutations in tumor DNA are associated with reduced survival after surgical treatment of squamous-cell carcinoma of the head and neck.
肿瘤抑制蛋白p53因其基因TP53发生突变而功能丧失，这是癌细胞中最常见的基因改变之一。我们评估了头颈部鳞状细胞癌患者的TP53突变情况及其生存率。
共有560名头颈部鳞状细胞癌患者入组我们的前瞻性多中心7年研究，这些患者接受了根治性手术治疗。使用Affymetrix p53芯片、Surveyor DNA内切酶和变性高效液相色谱法对肿瘤标本的DNA进行TP53突变分析。根据从p53-DNA复合物晶体结构预测的蛋白质结构干扰程度，将突变分为两组，即破坏性突变和非破坏性突变。将TP53突变状态与临床结果进行比较。
420例患者中有224例（53.3%）的肿瘤检测到TP53突变。与野生型TP53相比，任何TP53突变的存在均与总生存率降低相关（死亡风险比为1.4；95%置信区间[CI]为1.1至1.8；P=0.009），与破坏性突变的相关性更强（风险比为1.7；95%CI为1.3至2.4；P<0.001），与非破坏性突变无显著相关性（风险比为1.2；95%CI为0.9至1.7；P=0.16）。在多变量分析中，与无TP53突变相比，破坏性TP53改变与生存率降低具有独立的显著相关性（风险比为1.7；95%CI为1.2至2.4；P=0.003）。
肿瘤DNA中的破坏性TP53突变与头颈部鳞状细胞癌手术治疗后的生存率降低相关。
