Koch W M, Brennan J A, Zahurak M, Goodman S N, Westra W H, Schwab D, Yoo G H, Lee D J, Forastiere A A, Sidransky D
Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Hospital, Baltimore, MD 21205-2196, USA.
J Natl Cancer Inst. 1996 Nov 6;88(21):1580-6. doi: 10.1093/jnci/88.21.1580.
The p53 gene (also known as TP53) may be the most common genetic target involved in the malignant transformation of human cells. Direct sequence analysis has demonstrated that alteration of this gene occurs in approximately 45% of head and neck squamous cell carcinomas. The consequences of p53 mutations in these cancers with respect to tumor behavior and patient survival have not been rigorously determined.
We evaluated the implications of p53 mutations in relation to the control of locoregional disease and overall survival following radiation therapy.
Data from 110 consecutive patients with invasive disease who were treated with primary radiation therapy (given with curative intent) or with adjuvant radiation therapy (following complete surgical extirpation of gross disease) were included in the analysis. A 1.8-kilobase fragment of the p53 gene encompassing exons 5-9 was amplified from the DNA of stored (frozen) tumor specimens; the amplified DNA was cloned and sequenced by use of standard techniques. Overall survival and locoregional disease-free survival after the completion of radiation therapy were estimated by the Kaplan-Meier method; survival comparisons were made by use of the logrank test or proportional hazards regression models. Reported P values are two-sided.
Fortyeight (44%) of the 110 tumors had cells bearing p53 mutations. The risk of locoregional recurrence following either primary or adjuvant radiation therapy was significantly greater (i.e., the time to recurrence was shorter) for patients whose tumors contained mutant p53 genes (univariate model hazard ratio [HR] for p53 mutation versus wild-type = 2.2; 95% confidence interval [CI] = 1.2-4.1; P = .02). The presence of regional lymph node metastases (presence versus absence, HR = 2.0; 95% CI = 1.0-4.2; P = .05) and treatment type (primary radiation therapy versus surgery plus adjuvant radiation therapy, HR = 2.3; 95% CI = 1.2-4.3; P = .01) were also associated with greater risks of locoregional failure. The presence of p53 mutations and lymph node metastases and treatment with primary, as opposed to adjuvant, radiation therapy remained significant risk factors in multivariate regression analysis. No relationship was demonstrated between p53 status and overall survival (mutant versus wild-type, HR = 1.1; 95% CI = 0.6-2.1; P = .66); however, a relationship was shown for tumor stage and overall survival (stages III and IV [more advanced] versus stages I and II [less advanced], HR = 3.3; 95% CI = 1.0-10.8; P = .05). Mutation of the p53 gene was not associated with patient age, sex, tumor stage, primary tumor site, regional lymph node status, degree of tumor cell differentiation, or treatment method.
Mutation of the p53 gene is associated with an increased risk of locoregional failure in patients with invasive head and neck squamous cell carcinoma who are treated with radiation therapy.
p53基因（也称为TP53）可能是人类细胞恶性转化中最常见的基因靶点。直接序列分析表明，该基因的改变约发生在45%的头颈部鳞状细胞癌中。p53突变在这些癌症中对肿瘤行为和患者生存的影响尚未得到严格确定。
我们评估了p53突变对放疗后局部区域疾病控制和总生存的影响。
分析纳入了110例连续的侵袭性疾病患者的数据，这些患者接受了根治性原发性放疗或辅助性放疗（在大体疾病完全手术切除后进行）。从储存（冷冻）的肿瘤标本DNA中扩增包含外显子5 - 9的1.8千碱基片段的p53基因；扩增的DNA通过标准技术进行克隆和测序。放疗完成后的总生存和局部区域无病生存通过Kaplan-Meier方法估计；生存比较采用对数秩检验或比例风险回归模型。报告的P值为双侧。
110例肿瘤中有48例（44%）的细胞存在p53突变。肿瘤含有突变p53基因的患者，原发性或辅助性放疗后局部区域复发风险显著更高（即复发时间更短）（p53突变与野生型的单变量模型风险比[HR] = 2.2；95%置信区间[CI] = 1.2 - 4.1；P = 0.02）。区域淋巴结转移的存在（存在与不存在，HR = 2.0；95% CI = 1.0 - 4.2；P = 0.05）和治疗类型（原发性放疗与手术加辅助性放疗，HR = 2.3；95% CI = 1.2 - 4.3；P = 0.01）也与局部区域失败风险更高相关。在多变量回归分析中，p53突变、淋巴结转移的存在以及原发性而非辅助性放疗仍是显著的风险因素。未发现p53状态与总生存之间存在关联（突变型与野生型，HR = 1.1；95% CI = 0.6 - 2.1；P = 0.66）；然而，显示肿瘤分期与总生存之间存在关联（III期和IV期[更晚期]与I期和II期[较早期]，HR = 3.3；95% CI = 1.0 - 10.8；P = 0.05）。p53基因突变与患者年龄、性别、肿瘤分期、原发肿瘤部位、区域淋巴结状态、肿瘤细胞分化程度或治疗方法无关。
p53基因突变与接受放疗的侵袭性头颈部鳞状细胞癌患者局部区域失败风险增加相关。
