title: Whole-exome sequencing characterizes the landscape of somatic mutations and copy number alterations in adrenocortical carcinoma.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors.affiliation: 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.
authors.forename: C Christofer
authors.initials: CC
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authors.forename: Reju
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authors.forename: Catharina
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mesh_terms: D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000235:genetics*; D018268:Adrenocortical Carcinoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D056915:DNA Copy Number Variations; D059472:Exome / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017422:Sequence Analysis, DNA / Q000379:methods*; D055815:Young Adult