title: Chromosome 19 amplification correlates with advanced disease in adrenocortical carcinoma.
abstract: BACKGROUND
  Familial syndromes with specific genetic drivers account for a subset of adrenocortical carcinomas (ACCs), but the genomic underpinnings of sporadic cases remain poorly understood. Recent advances in copy number variation (CNV) prediction from exome sequencing are facilitating exploration of genomic rearrangements common to these carcinomas.
  
  
  METHODS
  ACC and matched, nontumor samples underwent exome sequencing. CNVs were predicted using coverage-depth comparison. Clinicopathologic characteristics of amplification- and deletion-dominant samples were compared and pathway enrichment analysis performed for regions with significant variation.
  
  
  RESULTS
  CNVs are distributed broadly across the ACC genome. Individual signatures demonstrate amplification or deletion dominance. Areas of recurrent amplification include chromosomes 5, 12, 19, and 20, whereas chromosomes 1, 10, 18, and 22 are deletion prone. Large-scale amplification of chromosome 19 occurred in 12 of 19 cases (63%), including 6 of 8 amplification-dominant samples (75%) and was associated with stage III/IV disease (P = .002). Genes within this amplified region are overrepresented among the adrenal hyperplasia and steroid biosynthesis pathways (P = 4.2(-5) and 2.5(-5), respectively).
  
  
  CONCLUSIONS
  CNV detection via exome sequencing allows high-resolution cataloging of structural variations in ACC. Large-scale, recurrent amplifications encompassing known adrenal-specific gene pathways correlate with tumor stage. Further functional analysis of individual genes within these regions could provide mechanistic insight into specific drivers underlying pathogenesis and progression of ACC.
authors.affiliation: Department of Surgery & Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, CT.
authors.forename: Jill C
authors.initials: JC
authors.lastname: Rubinstein
authors.affiliation: Department of Surgery & Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, CT.
authors.forename: Taylor C
authors.initials: TC
authors.lastname: Brown
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT.
authors.forename: Gerald
authors.initials: G
authors.lastname: Goh
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: C Christofer
authors.initials: CC
authors.lastname: Juhlin
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Adam
authors.initials: A
authors.lastname: Stenman
authors.affiliation: Department of Surgery & Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, CT.
authors.forename: Reju
authors.initials: R
authors.lastname: Korah
authors.affiliation: Department of Surgery & Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, CT. Electronic address: tobias.carling@yale.edu.
authors.forename: Tobias
authors.initials: T
authors.lastname: Carling
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics / Q000473:pathology*; D018268:Adrenocortical Carcinoma / Q000235:genetics / Q000473:pathology*; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D056915:DNA Copy Number Variations; D059472:Exome; D005260:Female; D005784:Gene Amplification; D006801:Humans; D008297:Male; D008875:Middle Aged