All-Exon TP53 Sequencing and Protein Phenotype Analysis Accurately Predict Clinical Outcome after Surgical Treatment of Head and Neck Squamous Cell Carcinoma
All-Exon TP53 Sequencing and Protein Phenotype Analysis Accurately Predict Clinical Outcome after Surgical Treatment of Head and Neck Squamous Cell Carcinoma
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DOI：
10.1245/s10434-019-07287-x
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发表时间：
2019-07-01
影响因子：
3.7
通讯作者：
Mori, Taisuke
中科院分区：
文献类型：
--
作者：
Kobayashi, Kenya;Yoshimoto, Seiichi;Mori, Taisuke
背景资料。本研究采用福尔马林固定石蜡包埋(FFPE)标本，通过对TP53基因所有外显子的详细搜索和P53蛋白表型分析，阐明手术治疗头颈部鳞状细胞癌(HNSCC)的临床影响。采用全外显子TP53测序仪对317例经手术治疗的HNSCC患者的FFPE标本进行全外显子TP53测序，并用免疫组织化学方法检测P53蛋白表型。在排除人乳头瘤病毒相关性口咽癌后，根据TP53突变状态和P53蛋白表型，将两种风险分类为“P53不利功能”和“P53有利功能”。通过靶序列检测PIK3CA、AKT和HRAS的突变情况。临床结果的统计分析采用COX比例风险回归模型。受试者操作特征曲线分析用于确定局部复发的最佳手术切缘。用Fisher‘s精确检验比较不同危险组的局部控制率。多变量分析表明，“P53功能不良”是总生存率、局部控制率和无远处转移生存率的独立不良预测因子。在口腔癌中，与局部复发相关的最佳手术切缘为6 mm。在手术切缘<6 mm的患者中，“P53功能不良”组的局部复发率显著高于“P53功能良好组”。PIK3CA、AKT或HRAS突变与总生存率的改善无关。结论：利用FFPE标本进行全外显子TP53测序和P53蛋白表型分析可以准确地预测临床结果。
Background. This study elucidates the clinical impact of surgical treatment of head and neck squamous cell carcinoma (HNSCC) based on a detailed search of all exons of the TP53 gene and p53 protein phenotypic analysis using formalin-fixed paraffin-embedded (FFPE) specimens.Methods. Clinically well-annotated FFPE specimens from 317 patients with HNSCC treated by surgery were examined by all-exon TP53 sequencing using a next-generation sequencer and p53 protein phenotype by immunohistochemistry. After excluding human papillomavirus-associated oropharyngeal carcinomas, two risk categories were classified as "p53 adverse function" and "p53 favorable function" based on TP53 mutation status and p53 protein phenotype. Mutation in PIK3CA, AKT, and HRAS was also evaluated by target sequence. Cox proportional hazards regression models were used for statistical analysis of clinical outcomes. Receiver operating characteristic curve analysis was used to determine the optimal surgical margin cutoff for local recurrence. Local control rates were compared between the risk groups using Fisher's exact test.Results. Multivariate analysis identified "p53 adverse function" as an independent poor predictor of overall survival, local control, and distant metastasis-free survival. In oral cavity cancer, the optimal surgical margin cutoff associated with local recurrence was 6mm. In patients with surgical margin >6mm, the "p53 adverse function" group demonstrated significantly higher local recurrence rate than the "p53 favorable function group. PIK3CA, AKT, or HRAS mutation did not correlate with improved overall survival.Conclusions. All-exon TP53 sequencing and p53 protein phenotype analysis using FFPE specimens can accurately predict clinical outcomes.