Hospital Universitari Arnau de Vilanova, Universitat de Lleida, IRBLleida, Ciberonc, Lleida, Spain.
Hospital Universitari de Bellvitge, Idibell, Barcelona, Spain.
Histopathology. 2020 Feb;76(3):447-460. doi: 10.1111/his.14001. Epub 2020 Jan 13.
Endometrial serous carcinoma (ESC) represents the most aggressive subtype of endometrial carcinoma (EC). According to The Cancer Genome Atlas (TCGA), ESC exhibits a genomic profile characterised by frequent TP53 mutations and somatic copy-number alterations (SCNA). Several studies have suggested the role of intratumour heterogeneity (ITH) in tumour progression and therapy resistance, highlighting ITH as a challenge for personalised medicine. ITH is described as the co-existence of clonal and subclonal cellular populations within a single tumour. To date, the extent and prevalence of ITH in ESC have not been fully evaluated. The aim of this study was to address ITH analysis in ESC. We performed a descriptive integrated molecular approach using targeted sequencing and multiplex ligation-dependent probe amplification (MLPA) to identify mutations and SCNA patterns, respectively.
Eight ESC were examined, selecting three tumour regions per case and their corresponding normal tissue. For targeted sequencing a gene panel of 40 genes based on TCGA and other survey data was performed. For MLPA different probe mixes were used to detect SCNA in 106 genes. Analysis of mutations and SCNA were performed in each sample and comparative analysis of the three tumour regions was also conducted. Targeted sequencing showed that mutations in TP53, PIK3CA and PPP2R1A were ubiquitous in all tumour regions. Moreover, MLPA results demonstrated a high frequency of SCNA, according to the already known presence of genomic instability in ESC. Unlike the homogeneous distribution of somatic mutations, SCNA exhibited ITH affecting targetable genes such as ERBB2.
Our study suggests that somatic gene copy-number alterations are the main source of ITH in ESC.
子宫内膜浆液性癌（ESC）是子宫内膜癌（EC）中侵袭性最强的亚型。根据癌症基因组图谱（TCGA），ESC 表现出以 TP53 突变和体细胞拷贝数改变（SCNA）频繁发生为特征的基因组特征。几项研究表明肿瘤内异质性（ITH）在肿瘤进展和治疗耐药性中的作用，突出了 ITH 是个性化医学的挑战。ITH 被描述为单个肿瘤内克隆和亚克隆细胞群体的共存。迄今为止，尚未全面评估 ESC 中 ITH 的程度和普遍性。本研究旨在探讨 ESC 中的 ITH 分析。我们使用靶向测序和多重连接依赖性探针扩增（MLPA）分别进行了描述性的综合分子方法，以分别鉴定突变和 SCNA 模式。
检查了 8 例 ESC，每例选择 3 个肿瘤区域及其相应的正常组织。针对靶向测序，使用基于 TCGA 和其他调查数据的 40 个基因的基因面板进行。对于 MLPA，使用不同的探针混合物检测 106 个基因中的 SCNA。对每个样本进行突变和 SCNA 分析，并对三个肿瘤区域进行比较分析。靶向测序显示，TP53、PIK3CA 和 PPP2R1A 中的突变在所有肿瘤区域中普遍存在。此外，MLPA 结果表明 SCNA 发生频率很高，这与 ESC 中已知的基因组不稳定性存在一致。与体细胞突变的均匀分布不同，SCNA 表现出 ITH，影响 ERBB2 等可靶向基因。
我们的研究表明，体细胞基因拷贝数改变是 ESC 中 ITH 的主要来源。
