Intraindividual genomic heterogeneity of high-grade serous carcinoma of the ovary and clinical utility of ascitic cancer cells for mutation profiling
Intraindividual genomic heterogeneity of high-grade serous carcinoma of the ovary and clinical utility of ascitic cancer cells for mutation profiling
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DOI：
10.1002/path.4819
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发表时间：
2017-01-01
影响因子：
7.3
通讯作者：
Lee, Sug Hyung
中科院分区：
文献类型：
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作者：
Choi, Youn Jin;Rhee, Je-Keun;Lee, Sug Hyung
个体内肿瘤异质性（ITH）是实体瘤的一个标志，阻碍了准确的基因组诊断和正确治疗的选择。本研究的目的是鉴定卵巢高级别浆液性癌 (OSC) 的 ITH，并确定腹水癌细胞作为突变谱资源的实用性（尽管存在 ITH）。我们使用来自 13 个卵巢内病变、12 个卵巢外肿瘤病变（大网膜/腹膜）和腹水细胞的多区域活检，对 4 个 OSC 基因组进行了全外显子组测序、拷贝数分析和 DNA 甲基化分析。我们观察到 OSC 的突变和拷贝数改变 (CNA) 存在显着的异质性。我们根据区域分布将突变分为“公共”、“共享”和“私有”。在已知的癌症相关基因中观察到 6 个常见突变、8 个共享突变和 24 个私有突变。常见突变具有较高的突变等位基因频率，并且在所有四个 OSC 中都包括 TP53 突变。还鉴定了涉及 BRCA1、PIK3CA 和 RB1 的区域特异性染色体扩增和缺失。值得注意的是，在给定病例中，腹水癌细胞中检测到的突变占总体体细胞突变的 92.3-100%。腹水基因组的系统发育分析预测了腹水细胞体细胞突变的多播起源。我们的结果表明，尽管存在 ITH，但常见类别和癌症相关基因中的体细胞突变、CNA 和 DNA 甲基化在 OSC 腹水细胞中高度保守，凸显了腹水细胞基因组分析的临床相关性。腹水肿瘤细胞可能作为发现具有诊断和治疗相关性的原发性 OSC 体细胞突变的潜在资源。版权所有 (c) 2016 大不列颠及爱尔兰病理学会。由约翰·威利父子有限公司出版
Intraindividual tumoural heterogeneity (ITH) is a hallmark of solid tumours and impedes accurate genomic diagnosis and selection of proper therapy. The aim of this study was to identify ITH of ovarian high-grade serous carcinomas (OSCs) and to determine the utility of ascitic cancer cells as a resource for mutation profiling in spite of ITH. We performed whole-exome sequencing, copy number profiling and DNA methylation profiling of four OSC genomes by using multiregional biopsies from 13 intraovarian lesions, 12 extraovarian tumour lesions (omentum/peritoneum), and ascitic cells. We observed substantial levels of heterogeneity in mutations and copy number alterations (CNAs) of the OSCs. We categorized the mutations into common', shared' and private' according to the regional distribution. Six common, eight shared and 24 private mutations were observed in known cancer-related genes. Common mutations had a higher mutant allele frequency, and included TP53 mutations in all four OSCs. Region-specific chromosomal amplifications and deletions involving BRCA1, PIK3CA and RB1 were also identified. It is of note that the mutations detected in ascitic cancer cells represented 92.3-100% of overall somatic mutations in the given case. Phylogenetic analyses of ascitic genomes predicted a polyseeding origin of somatic mutations in ascitic cells. Our results demonstrate that, despite ITH, somatic mutations, CNAs and DNA methylations in both common' category and cancer-related genes were highly conserved in ascitic cells of OSCs, highlighting the clinical relevance of genome analysis of ascitic cells. Ascitic tumour cells may serve as a potential resource for discovering somatic mutations of primary OSC with diagnostic and therapeutic relevance. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.