Targeted Genomic Sequencing Reveals Novel TP53 In-frame Deletion Mutations Leading to p53 Overexpression in High-grade Serous Tubo-ovarian Carcinoma
Targeted Genomic Sequencing Reveals Novel TP53 In-frame Deletion Mutations Leading to p53 Overexpression in High-grade Serous Tubo-ovarian Carcinoma
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DOI：
10.21873/anticanres.13417
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发表时间：
2019-06-01
影响因子：
2
通讯作者：
Kim, Hyun-Soo
中科院分区：
文献类型：
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作者：
Jung, Yoon Yang;Woo, Ha Young;Kim, Hyun-Soo
背景/目的：高级浆液性癌（HGSC）是卵巢癌最常见的组织学亚型。肿瘤蛋白53（TP 53）的体细胞突变是输卵管卵巢HGSC的标志，并且在几乎所有此类病例中观察到。高度敏感的靶向基因组测序可用于鉴定可能成为潜在药物靶点的新突变，并有助于治疗决策。本研究的目的是描述HGSCs的临床病理学和分子特征与新的体细胞TP 53突变确定的下一代测序（NGS）。材料与方法：使用包括TP 53在内的170个基因的商业NGS面板分析132例卵巢癌病例的遗传谱。对两例TP 53突变的HGSCs的临床病理特征和p53免疫组化结果进行了研究。结果：132例卵巢癌患者中88例（66.7%）诊断为HGSC。新的TP 53读框内缺失突变c.719_727delGTTCCTGCA（p53 p.Ser240_Cys242del）和c.634_642delTTTCGACAT（p53 p.F212_H214del）在单个HGSC病例中检测到。2例患者均为绝经后女性。影像学和实验室检查显示腹膜癌转移和血清肿瘤标志物水平升高。患者接受了初次减瘤手术，并被诊断为IIIC期HGSC。在这两种情况下，p53免疫染色显示，在90%或更多的肿瘤细胞在一个非常强的强度均匀的核免疫反应。结论：靶向基因组测序揭示了导致输卵管卵巢HGSC中p53过表达的TP 53框内缺失突变。这一先前未报道的体细胞TP 53突变的发现为NGS技术转化为个性化医疗提供了见解，并为治疗应用确定了新的潜在靶点。
Background/Aim: High-grade serous carcinoma (HGSC) is the most common histological subtype of ovarian carcinoma. Somatic mutation of tumor protein 53 (TP53) is a hallmark of tubo-ovarian HGSC and is observed in almost all such cases. Highly sensitive targeted genomic sequencing can be used to identify novel mutations that may become potential druggable targets and aid in therapeutic decisions. The aim of this study was to describe the clinicopathological and molecular characteristics of HGSCs with novel somatic TP53 mutations identified by next-generation sequencing (NGS). Materials and Methods: A commercial NGS panel comprising 170 genes, including TP53, was used to analyze the genetic profiles of 132 ovarian carcinoma cases. The clinicopathological characteristics and p53 immunostaining results of two HGSCs exhibiting novel TP53 mutations were investigated. Results: Eighty-eight (66.7%) out of 132 ovarian carcinoma cases were diagnosed as HGSC. Novel TP53 in-frame deletion mutations c.719_727delGTTCCTGCA (p53 p.Ser240_Cys242del) and c.634_642delTTTCGACAT (p53 p.F212_H214del) were detected in a single case of HGSC each. Both patients were postmenopausal women. Imaging and laboratory studies revealed peritoneal carcinomatosis and elevated levels of serum tumor markers. The patients underwent primary debulking surgery and were diagnosed as having stage IIIC HGSC. In both cases, p53 immunostaining revealed uniform nuclear immunoreactivity in 90% or more of tumor cells at a very strong intensity. Conclusion: Targeted genomic sequencing revealed novel in-frame deletion mutations of TP53 leading to p53 overexpression in tubo-ovarian HGSC. This discovery of previously unreported somatic TP53 mutations provides insight into the translation of NGS technology into personalized medicine and identifies new potential targets for therapeutic applications.