Juhlin C Christofer, Goh Gerald, Healy James M, Fonseca Annabelle L, Scholl Ute I, Stenman Adam, Kunstman John W, Brown Taylor C, Overton John D, Mane Shrikant M, Nelson-Williams Carol, Bäckdahl Martin, Suttorp Anna-Carinna, Haase Matthias, Choi Murim, Schlessinger Joseph, Rimm David L, Höög Anders, Prasad Manju L, Korah Reju, Larsson Catharina, Lifton Richard P, Carling Tobias
Yale Endocrine Neoplasia Laboratory (C.C.J., J.M.H., A.L.F., J.W.K., T.C.B., R.K., T.C.), Yale School of Medicine, New Haven, Connecticut 06520; Department of Surgery (C.C.J., J.M.H., A.L.F., J.W.K., T.C.B., R.K., T.C.), Yale School of Medicine, New Haven, Connecticut, 06520; Department of Genetics (G.G., C.N.W., M.C., R.P.L.), Yale School of Medicine and Howard Hughes Medical Institute, New Haven, Connecticut, 06520; Department of Oncology-Pathology (C.C.J., A.S., A.H., C.L.), Karolinska Institutet, Karolinska University Hospital, CCK, SE-171 76 Stockholm, Sweden; Yale Center for Genome Analysis (JDO, SMM), Orange, Connecticut, 06477; Department of Pathology (D.L.R., M.L.P.), Yale School of Medicine, New Haven, Connecticut, 06520; Department of Pharmacology (J.S.), Yale School of Medicine, New Haven, Connecticut 06520; Department of Molecular Medicine and Surgery (M.B.), Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Division of Nephrology (U.I.S.), University Hospital Düsseldorf, 40225 Düsseldorf, Germany; Department of Pathology (A.C.S.), University Hospital Düsseldorf, 40225 Düsseldorf, Germany; and Division of Endocrinology and Diabetology (M.H.), University Hospital Düsseldorf, 40225 Düsseldorf, Germany.
J Clin Endocrinol Metab. 2015 Mar;100(3):E493-502. doi: 10.1210/jc.2014-3282. Epub 2014 Dec 9.
Adrenocortical carcinoma (ACC) is a rare and lethal malignancy with a poorly defined etiology, and the molecular genetics of ACC are incompletely understood.
To utilize whole-exome sequencing for genetic characterization of the underlying somatic mutations and copy number alterations present in ACC.
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.
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.
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.
肾上腺皮质癌（ACC）是一种罕见的致命性恶性肿瘤，其病因尚不明确，ACC的分子遗传学也未完全了解。
利用全外显子组测序对ACC中存在的潜在体细胞突变和拷贝数改变进行基因特征分析。
通过对41例ACC患者的肿瘤组织和配对的正常样本进行比较分析，筛查体细胞突变事件和拷贝数改变（CNA）。
共检测到966个非同义体细胞突变，其中40个肿瘤样本平均每个样本有16个突变，1个肿瘤样本有314个突变。ACC相关基因的体细胞突变包括TP53（8/41个肿瘤，19.5%）和CTNNB1（4/41，9.8%）。具有潜在致病突变的基因包括GNAS、NF2和RB1，在肿瘤发生中作用未知但反复突变的基因包括CDC27、SCN7A和SDK1。反复出现的CNA包括5p15.33区域的扩增，包括TERT（6/41，14.6%）以及22q12.1区域的纯合缺失，包括Wnt抑制因子ZNRF3和KREMEN1（分别为4/41，9.8%和3/41，7.3%）。在大多数情况下，ACC既定基因中的体细胞突变与反复出现的ZNRF3和TERT基因座CNA相互排斥。此外，基因本体分析确定Wnt信号通路是ACC中最常发生突变的途径。
这些发现突出了Wnt通路失调在ACC中的重要性，并证实了Wnt抑制因子ZNRF3和KREMEN1纯合缺失的发现。总体而言，TP53或CTNNB1的突变以及ZNRF3或TERT基因座的局灶性CNA表示相互排斥的事件，提示这些肿瘤发生的潜在机制不同。
