title: Next-generation sequencing of adrenocortical carcinoma reveals new routes to targeted therapies.
abstract: OBJECTIVE
  Adrenocortical carcinoma (ACC) carries a poor prognosis and current systemic cytotoxic therapies result in only modest improvement in overall survival. In this retrospective study, we performed a comprehensive genomic profiling of 29 consecutive ACC samples to identify potential targets of therapy not currently searched for in routine clinical practice.
  
  
  METHODS
  DNA from 29 ACC was sequenced to high, uniform coverage (Illumina HiSeq) and analysed for genomic alterations (GAs).
  
  
  RESULTS
  At least one GA was found in 22 (76%) ACC (mean 2.6 alterations per ACC). The most frequent GAs were in TP53 (34%), NF1 (14%), CDKN2A (14%), MEN1 (14%), CTNNB1 (10%) and ATM (10%). APC, CCND2, CDK4, DAXX, DNMT3A, KDM5C, LRP1B, MSH2 and RB1 were each altered in two cases (7%) and EGFR, ERBB4, KRAS, MDM2, NRAS, PDGFRB, PIK3CA, PTEN and PTCH1 were each altered in a single case (3%). In 17 (59%) of ACC, at least one GA was associated with an available therapeutic or a mechanism-based clinical trial.
  
  
  CONCLUSIONS
  Next-generation sequencing can discover targets of therapy for relapsed and metastatic ACC and shows promise to improve outcomes for this aggressive form of cancer.
authors: Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors: J S
authors: JS
authors: Ross
authors: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors: K
authors: K
authors: Wang
authors: Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors: J V
authors: JV
authors: Rand
authors: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors: L
authors: L
authors: Gay
authors: Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors: M J
authors: MJ
authors: Presta
authors: Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors: C E
authors: CE
authors: Sheehan
authors: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors: S M
authors: SM
authors: Ali
authors: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors: J A
authors: JA
authors: Elvin
authors: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors: E
authors: E
authors: Labrecque
authors: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors: C
authors: C
authors: Hiemstra
authors: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors: J
authors: J
authors: Buell
authors: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors: G A
authors: GA
authors: Otto
authors: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors: R
authors: R
authors: Yelensky
authors: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors: D
authors: D
authors: Lipson
authors: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors: D
authors: D
authors: Morosini
authors: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors: J
authors: J
authors: Chmielecki
authors: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors: V A
authors: VA
authors: Miller
authors: Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
authors: P J
authors: PJ
authors: Stephens
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001706:Biopsy; D015195:Drug Design; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D018579:Patient Selection; D057285:Precision Medicine; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor
keywords: Cancer Genetics; Endocrine Pathology; Gene Amplification; Molecular Pathology; Oncology