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Abstract：
Alterations in the tumor suppressor TP53 gene are the most common mutations in high grade serous ovarian carcinoma. The impact of TP53 mutations on clinical outcomes and platinum resistance is controversial. We sought to evaluate the genomic profile of high grade serous ovarian carcinoma and explore the association of TP53 mutations with platinum resistance.
Next generation sequencing data was obtained from our institutional database for patients with high grade serous ovarian carcinoma undergoing primary treatment. Sequencing data, demographic, and clinical information was reviewed. The primary outcome analyzed was time to recurrence or refractory diagnosis. Associations between the primary outcome and different classification schemes for TP53 mutations (structural, functional, hot spot, pathogenicity scores, immunohistochemical staining patterns) were performed.
209 patients met inclusion criteria. TP53 mutations were the most common mutation. There were no differences in platinum response with TP53 hotspot mutations or high pathogenicity scores. Presence of TP53 gain-of-function mutations or measure of TP53 gain-of function activity were not associated with platinum resistance. Immunohistochemical staining patterns correlated with expected TP53 protein function and were not associated with platinum resistance.
TP53 hotspot mutations or high pathogenicity scores were not associated with platinum resistance or refractory disease. Contrary to prior studies, TP53 gain-of-function mutations were not associated with platinum resistance. Estimation of TP53 gain-of-function effect using missense mutation phenotype scores was not associated with platinum resistance. The polymorphic nature of TP53 mutations may be too complex to demonstrate effect using simple models, or response to platinum therapy may be independent of initiating TP53 mutation.
Next generation sequencing data was obtained from our institutional database for patients with high grade serous ovarian carcinoma undergoing primary treatment. Sequencing data, demographic, and clinical information was reviewed. The primary outcome analyzed was time to recurrence or refractory diagnosis. Associations between the primary outcome and different classification schemes for TP53 mutations (structural, functional, hot spot, pathogenicity scores, immunohistochemical staining patterns) were performed.
209 patients met inclusion criteria. TP53 mutations were the most common mutation. There were no differences in platinum response with TP53 hotspot mutations or high pathogenicity scores. Presence of TP53 gain-of-function mutations or measure of TP53 gain-of function activity were not associated with platinum resistance. Immunohistochemical staining patterns correlated with expected TP53 protein function and were not associated with platinum resistance.
TP53 hotspot mutations or high pathogenicity scores were not associated with platinum resistance or refractory disease. Contrary to prior studies, TP53 gain-of-function mutations were not associated with platinum resistance. Estimation of TP53 gain-of-function effect using missense mutation phenotype scores was not associated with platinum resistance. The polymorphic nature of TP53 mutations may be too complex to demonstrate effect using simple models, or response to platinum therapy may be independent of initiating TP53 mutation.
摘要：
目的：肿瘤抑制基因TP53的改变是高级别浆液性卵巢癌中最常见的突变。TP53突变对临床结果和铂类耐药的影响存在争议。我们试图评估高级别浆液性卵巢癌的基因组谱，并探索TP53突变与铂耐药的关联。
方法：下一代测序数据来自我们的机构数据库，用于接受初级治疗的高级别浆液性卵巢癌患者。测序数据,人口统计学,并回顾了临床资料。分析的主要结果是复发或难治性诊断的时间。主要结果与TP53突变的不同分类方案之间的关联（结构，功能，热点,致病性评分，进行免疫组织化学染色模式）。
结果：209例患者符合纳入标准。TP53突变是最常见的突变。TP53热点突变或高致病性评分的铂反应没有差异。TP53功能获得突变的存在或TP53功能获得活性的测量与铂抵抗无关。免疫组织化学染色模式与预期的TP53蛋白功能相关，与铂抵抗无关。
结论：TP53热点突变或高致病性评分与铂类耐药或难治性疾病无关。与以前的研究相反，TP53功能获得突变与铂耐药无关。使用错义突变表型评分估计TP53功能获得效应与铂抗性无关。TP53突变的多态性质可能太复杂，无法使用简单的模型证明效果。或对铂治疗的反应可能与TP53突变的起始无关。
方法：下一代测序数据来自我们的机构数据库，用于接受初级治疗的高级别浆液性卵巢癌患者。测序数据,人口统计学,并回顾了临床资料。分析的主要结果是复发或难治性诊断的时间。主要结果与TP53突变的不同分类方案之间的关联（结构，功能，热点,致病性评分，进行免疫组织化学染色模式）。
结果：209例患者符合纳入标准。TP53突变是最常见的突变。TP53热点突变或高致病性评分的铂反应没有差异。TP53功能获得突变的存在或TP53功能获得活性的测量与铂抵抗无关。免疫组织化学染色模式与预期的TP53蛋白功能相关，与铂抵抗无关。
结论：TP53热点突变或高致病性评分与铂类耐药或难治性疾病无关。与以前的研究相反，TP53功能获得突变与铂耐药无关。使用错义突变表型评分估计TP53功能获得效应与铂抗性无关。TP53突变的多态性质可能太复杂，无法使用简单的模型证明效果。或对铂治疗的反应可能与TP53突变的起始无关。
