title: Patterns of chromosomal copy-number alterations in intrahepatic cholangiocarcinoma.
abstract: BACKGROUND
  Intrahepatic cholangiocarcinomas (ICC) are relatively rare malignant tumors associated with a poor prognosis. Recent studies using genome-wide sequencing technologies have mainly focused on identifying new driver mutations. There is nevertheless a need to investigate the spectrum of copy number aberrations in order to identify potential target genes in the altered chromosomal regions. The aim of this study was to characterize the patterns of chromosomal copy-number alterations (CNAs) in ICC.
  
  
  METHODS
  53 patients having ICC with frozen material were selected. In 47 cases, DNA hybridization has been performed on a genomewide SNP array. A procedure with a segmentation step and a calling step classified genomic regions into copy-number aberration states. We identified the exclusively amplified and deleted recurrent genomic areas. These areas are those showing the highest estimated propensity level for copy loss (resp. copy gain) together with the lowest level for copy gain (resp. copy loss). We investigated ICC clustering. We analyzed the relationships between CNAs and clinico-pathological characteristics.
  
  
  RESULTS
  The overall genomic profile of ICC showed many alterations with higher rates for the deletions. Exclusively deleted genomic areas were 1p, 3p and 14q. The main exclusively amplified genomic areas were 1q, 7p, 7q and 8q. Based on the exclusively deleted/amplified genomic areas, a clustering analysis identified three tumors groups: the first group characterized by copy loss of 1p and copy gain of 7p, the second group characterized by 1p and 3p copy losses without 7p copy gain, the last group characterized mainly by very few CNAs. From univariate analyses, the number of tumors, the size of the largest tumor and the stage were significantly associated with shorter time recurrence. We found no relationship between the number of altered cytobands or tumor groups and time to recurrence.
  
  
  CONCLUSIONS
  This study describes the spectrum of chromosomal aberrations across the whole genome. Some of the recurrent exclusive CNAs harbor candidate target genes. Despite the absence of correlation between CNAs and clinico-pathological characteristics, the co-occurence of 7p gain and 1p loss in a subgroup of patients may suggest a differential activation of EGFR and its downstream pathways, which may have a potential effect on targeted therapies.
authors: Laboratoire de Mathématiques et Modélisation d'Evry (LaMME), Université d'Evry Val d'Essonne, UMR CNRS 8071, USC INRA, Evry, France. cyril.dalmasso@genopole.cnrs.fr.
authors: Cyril
authors: C
authors: Dalmasso
authors: Plate-forme Post-Génomique P3S, UPMC, Faculté de Médecine, Paris, France. wassila.carpentier@upmc.fr.
authors: Wassila
authors: W
authors: Carpentier
authors: DHU Hepatinov, Centre Hépato-Biliaire, Hôpital Paul Brousse, AP-HP, Villejuif, France. catherine.guettier@bct.aphp.fr.|Faculté de Médecine, Univ. Paris-Sud, Kremlin-Bicêtre, France. catherine.guettier@bct.aphp.fr.
authors: Catherine
authors: C
authors: Guettier
authors: Department of Pathology, McGill University, Montreal, Canada. sophie.camilleri-broet@mcgill.ca.
authors: Sophie
authors: S
authors: Camilleri-Broët
authors: Faculté de Médecine, Univ. Paris-Sud, Kremlin-Bicêtre, France. wyllians.vb@gmail.com.|Faculdade de Medicina, Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil. wyllians.vb@gmail.com.
authors: Wyllians Vendramini
authors: WV
authors: Borelli
authors: Faculté de Médecine, Univ. Paris-Sud, Kremlin-Bicêtre, France. santoscedalia@gmail.com.|Faculdade de Medicina, Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil. santoscedalia@gmail.com.
authors: Cedália Rosane
authors: CR
authors: Campos Dos Santos
authors: DHU Hepatinov, Centre Hépato-Biliaire, Hôpital Paul Brousse, AP-HP, Villejuif, France. denis.castaing@pbr.aphp.fr.|Faculté de Médecine, Univ. Paris-Sud, Kremlin-Bicêtre, France. denis.castaing@pbr.aphp.fr.
authors: Denis
authors: D
authors: Castaing
authors: DHU Hepatinov, Centre Hépato-Biliaire, Hôpital Paul Brousse, AP-HP, Villejuif, France. jean-charles.duclos-vallee@pbr.aphp.fr.|Faculté de Médecine, Univ. Paris-Sud, Kremlin-Bicêtre, France. jean-charles.duclos-vallee@pbr.aphp.fr.
authors: Jean-Charles
authors: JC
authors: Duclos-Vallée
authors: Faculté de Médecine, Univ. Paris-Sud, Kremlin-Bicêtre, France. philippe.broet@inserm.fr.|DHU Hepatinov, UF Biostatistiques, Hôpital Paul Brousse, AP-HP, Villejuif, France. philippe.broet@inserm.fr.|INSERM UMR-669, Villejuif, France. philippe.broet@inserm.fr.
authors: Philippe
authors: P
authors: Broët
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D001650:Bile Duct Neoplasms / Q000209:etiology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018281:Cholangiocarcinoma / Q000209:etiology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002869:Chromosome Aberrations; D019295:Computational Biology / Q000379:methods; D056915:DNA Copy Number Variations; D005260:Female; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D047368:Tumor Burden