Whole-Exome Sequencing Characterizes the Landscape of Somatic Mutations and Copy Number Alterations in Adrenocortical Carcinoma
Whole-Exome Sequencing Characterizes the Landscape of Somatic Mutations and Copy Number Alterations in Adrenocortical Carcinoma
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DOI：
10.1210/jc.2014-3282
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发表时间：
2015-03-01
影响因子：
5.8
通讯作者：
Carling, Tobias
中科院分区：
文献类型：
--
作者：
Juhlin, C. Christofer;Goh, Gerald;Carling, Tobias
内容：肾上腺皮质癌（Adrenocortical carcinoma，ACC）是一种罕见的恶性肿瘤，其病因学尚不清楚，其分子遗传学研究尚不完全。目的：利用全外显子组测序技术对ACC中潜在的体细胞突变和拷贝数改变进行遗传学表征。设计：筛选体细胞突变事件和拷贝数改变（CNA）通过对41例ACC患者的肿瘤和匹配的正常标本进行比较分析。总共检测到966个非同义体细胞突变，包括40个肿瘤，每个样本平均16个突变，1个肿瘤有314个突变。ACC相关基因的体细胞突变包括TP 53（8/41，19.5%）和CTNNB 1（4/41，9.8%）。具有潜在致病突变的基因包括GNAS、NF 2和RB 1，在肿瘤发生中具有未知作用的复发突变基因包括CDC 27、SCN 7A和SDK 1。复发性CNA包括5p15.33扩增（包括TERT）（6/41，14.6%）和22q12.1纯合缺失（包括Wnt阻遏物ZNRF 3和KREMEN 1）（分别为4/41，9.8%和3/41，7.3%）。ACC建立的基因和复发性ZNRF 3和TERT基因座CNA的体细胞突变在大多数情况下是相互排斥的。此外，基因本体论确定Wnt信号作为最常见的突变途径ACCs.Conclusions：这些研究结果突出了Wnt通路失调的重要性，ACC和证实的Wnt阻遏物ZNRF 3和KREMEN 1的纯合缺失的发现。总体而言，TP 53或CTNNB 1突变以及ZNRF 3或TERT位点的局灶性CNA表示相互排斥的事件，表明这些肿瘤发生的独立机制。
Context: Adrenocortical carcinoma (ACC) is a rare and lethal malignancy with a poorly defined etiology, and the molecular genetics of ACC are incompletely understood.Objective: To utilize whole-exome sequencing for genetic characterization of the underlying somatic mutations and copy number alterations present in ACC.Design: Screening for somatic mutation events and copy number alterations (CNAs) was performed by comparative analysis of tumors and matched normal samples from 41 patients with ACC.Results: In total, 966 nonsynonymous somatic mutations were detected, including 40 tumors with a mean of 16 mutations per sample and one tumor with 314 mutations. Somatic mutations in ACC-associated genes included TP53 (8/41 tumors, 19.5%) and CTNNB1 (4/41, 9.8%). Genes with potential disease-causing mutations included GNAS, NF2, and RB1, and recurrently mutated genes with unknown roles in tumorigenesis comprised CDC27, SCN7A, and SDK1. Recurrent CNAs included amplification at 5p15.33 including TERT (6/41, 14.6%) and homozygous deletion at 22q12.1 including the Wnt repressors ZNRF3 and KREMEN1 (4/41 9.8% and 3/41, 7.3%, respectively). Somatic mutations in ACC-established genes and recurrent ZNRF3 and TERT loci CNAs were mutually exclusive in the majority of cases. Moreover, gene ontology identified Wnt signaling as the most frequently mutated pathway in ACCs.Conclusions: These findings highlight the importance of Wnt pathway dysregulation in ACC and corroborate the finding of homozygous deletion of Wnt repressors ZNRF3 and KREMEN1. Overall, mutations in either TP53 or CTNNB1 as well as focal CNAs at the ZNRF3 or TERT loci denote mutually exclusive events, suggesting separate mechanisms underlying the development of these tumors.