Pre-Invasive Ovarian Mucinous Tumors Are Characterized by CDKN2A and RAS Pathway Aberrations
Pre-Invasive Ovarian Mucinous Tumors Are Characterized by CDKN2A and RAS Pathway Aberrations
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DOI：
10.1158/1078-0432.ccr-12-1103
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发表时间：
2012-10-01
影响因子：
11.5
通讯作者：
Campbell, Ian G.
中科院分区：
文献类型：
--
作者：
Hunter, Sally M.;Gorringe, Kylie L.;Campbell, Ian G.
简介：粘液性肿瘤是第二常见的上皮性卵巢肿瘤，但这种组织学亚型的起源细胞仍不确定。虽然这些肿瘤被认为是通过从良性囊腺瘤到交界性肿瘤再到浸润性癌的逐步进展而产生的，但很少有研究试图全面表征这种亚型或其前体的特异性遗传变化。为了探索粘液性肿瘤常见的基因组改变谱，我们进行了高分辨率全基因组拷贝数分析，通过桑格测序和免疫组化对一系列原发性卵巢粘液性囊腺瘤（n = 20）和交界性肿瘤（n = 22）进行突变筛查。整合拷贝数数据，RAS/RAF通路成员的靶向突变筛查和免疫组织化学显示，p16丢失和RAS/RAF通路成员的突变可能与RAS/RAF通路成员的突变有关。RAF通路改变是在粘液性肿瘤发展早期发生的高度复发性事件。这些事件的并发症的频率观察到40%的良性囊腺瘤和68%的交界性tumors.Conclusions：这项研究是迄今为止进行的粘液性良性和交界性肿瘤的最大和最高分辨率的分析，并提供了强有力的支持，这些病变的前体原发性卵巢粘液腺癌。粘液性卵巢肿瘤发病机制的分子事件的高度一致性为靶向特定突变和途径的治疗提供了机会。临床癌症研究; 18（19）; 5267-77。（C）2012年AACR。
Introduction: Mucinous tumors are the second most common form of epithelial ovarian tumor, yet the cell of origin for this histologic subtype remains undetermined. Although these tumors are thought to arise through a stepwise progression from benign cystadenoma to borderline tumor to invasive carcinoma, few studies have attempted to comprehensively characterize the genetic changes specific to this subtype or its precursors.Methods: To explore the spectrum of genomic alterations common to mucinous tumors we carried out high-resolution genome-wide copy number analysis, mutation screening by Sanger sequencing and immunohistochemistry on a series of primary ovarian mucinous cystadenomas (n = 20) and borderline tumors (n = 22).Results: Integration of copy number data, targeted mutation screening of RAS/RAF pathway members and immunohistochemistry reveals that p16 loss and RAS/RAF pathway alterations are highly recurrent events that occur early during mucinous tumor development. The frequency of concurrence of these events was observed in 40% of benign cystadenomas and 68% of borderline tumors.Conclusions: This study is the largest and highest resolution analysis of mucinous benign and borderline tumors carried out to date and provides strong support for these lesions being precursors of primary ovarian mucinous adenocarcinoma. The high level of uniformity in the molecular events underlying the pathogenesis of mucinous ovarian tumors provides an opportunity for treatments targeting specific mutations and pathways. Clin Cancer Res; 18(19); 5267-77. (C)2012 AACR.