title: Molecular clonality analysis of esophageal adenocarcinoma by multiregion sequencing of tumor samples.
abstract: BACKGROUND
  Intratumor heterogeneity has been demonstrated in several cancer types, following a model of branched evolution. It is unknown to which extent intratumor heterogeneity is applicable to esophageal adenocarcinoma. Therefore the aim of this study was to characterise intratumor heterogeneity in esophageal adenocarcinoma.
  
  
  METHODS
  Multiregional targeted sequencing of four commonly altered genes was performed on 19 tumor regions collected from five esophageal adenocarcinomas. Alterations were classified as homogeneous or heterogeneous based on mutational and loss of heterozygosity analysis.
  
  
  RESULTS
  Identical TP53 mutations and homogeneously loss of heterozygosity of the TP53 locus were identified in all separated tumor regions in each of five adenocarcinomas, and in the corresponding Barrett's esophagus and tumor positive lymph node of one primary tumor. Loss of heterozygosity of the P16 locus was homogeneous among all tumor regions in four adenocarcinomas, and an identical pattern of loss of heterozygosity was present in the Barrett's esophagus. Loss of heterozygosity of the SMAD4 and APC loci was observed in a heterogeneous pattern.
  
  
  CONCLUSIONS
  Known driver alterations, such as TP53 and P16 are homogeneously present within each adenocarcinoma, and therefore occur early during carcinogenesis and subsequently clonally expand throughout the entire tumor. However, loss of heterozygosity of the SMAD4 and APC loci shows a heterogeneous pattern, indicating intratumor heterogeneity of esophageal adenocarcinoma.
authors.affiliation: Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.|Department of Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Anna M J
authors.initials: AM
authors.lastname: van Nistelrooij
authors.affiliation: Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: van Marion
authors.affiliation: Department of Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Linetta B
authors.initials: LB
authors.lastname: Koppert
authors.affiliation: Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Katharina
authors.initials: K
authors.lastname: Biermann
authors.affiliation: Department of Gastroenterology & Hepatology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Manon C W
authors.initials: MC
authors.lastname: Spaander
authors.affiliation: Department of Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Hugo W
authors.initials: HW
authors.lastname: Tilanus
authors.affiliation: Department of Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: J Jan B
authors.initials: JJ
authors.lastname: van Lanschot
authors.affiliation: Department of Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Bas P L
authors.initials: BP
authors.lastname: Wijnhoven
authors.affiliation: Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands. w.dinjens@erasmusmc.nl.
authors.forename: Winand N M
authors.initials: WN
authors.lastname: Dinjens
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D001471:Barrett Esophagus / Q000235:genetics / Q000378:metabolism; D060965:Clonal Evolution; D002999:Clone Cells; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis / Q000379:methods; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018740:Genetic Heterogeneity; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D051901:Smad4 Protein / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D019941:Cyclin-Dependent Kinase Inhibitor p16; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: Barrett’s esophagus; Clonality analysis; Esophageal adenocarcinoma; Intratumor heterogeneity