title: Cancers of unknown primary origin (CUP) are characterized by chromosomal instability (CIN) compared to metastasis of know origin.
abstract: BACKGROUND
  Cancers of unknown primary (CUPs) constitute ~5% of all cancers. The tumors have an aggressive biological and clinical behavior. The aim of the present study has been to uncover whether CUPs exhibit distinct molecular features compared to metastases of known origin.
  
  
  METHODS
  Employing genome wide transcriptome analysis, Linear Discriminant Analysis (LDA) and Quadratic Discriminant Analysis (QDA), we defined the putative origins of a large series of CUP and how closely related a particular CUP was to corresponding metastases of known origin. LDA predictions were subsequently used to define a universal CUP core set of differentially expressed genes, that by means of gene set enrichment analysis was exploited to depict molecular pathways characterizing CUP.
  
  
  RESULTS
  The analyses show that CUPs are distinct from metastases of known origin. CUPs exhibit inconsistent expression of conventional cancer biomarkers and QDA derived outlier scores show that CUPs are more distantly related to their primary tumor class than corresponding metastases of known origin. Gene set enrichment analysis showed that CUPs display increased expression of genes involved in DNA damage repair and mRNA signatures of chromosome instability (CIN), indicating that CUPs are chromosome unstable compared to metastases of known origin.
  
  
  CONCLUSIONS
  CIN may account for the uncommon clinical presentation, chemoresistance and poor outcome in patients with CUP and warrant selective diagnostic strategies and treatment.
authors.affiliation: Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen Ø, Denmark. jonas.vikesaa@regionh.dk.
authors.forename: Jonas
authors.initials: J
authors.lastname: Vikeså
authors.affiliation: Department of Oncology, University of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen Ø, Denmark. anne.kirstine.moeller@regionh.dk.
authors.forename: Anne Kirstine H
authors.initials: AK
authors.lastname: Møller
authors.affiliation: Bioinformatics Centre, Department of Biology and Biotech Research and Innovation Centre, University of Copenhagen, DK-2200, Copenhagen, Denmark. b.kaczkowski@gmail.com.
authors.forename: Bogumil
authors.initials: B
authors.lastname: Kaczkowski
authors.affiliation: Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen Ø, Denmark. rehannah.borup@regionh.dk.
authors.forename: Rehannah
authors.initials: R
authors.lastname: Borup
authors.affiliation: Department of Oncology, University of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen Ø, Denmark. ole.winther@gmail.com.|Technical University of Denmark (DTU), DK-2800, Lyngby, Denmark. ole.winther@gmail.com.
authors.forename: Ole
authors.initials: O
authors.lastname: Winther
authors.affiliation: Department of Oncology, University of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen Ø, Denmark. rhenao@binf.ku.dk.|Technical University of Denmark (DTU), DK-2800, Lyngby, Denmark. rhenao@binf.ku.dk.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Henao
authors.affiliation: Department of Oncology, University of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen Ø, Denmark. krogh@binf.ku.dk.
authors.forename: Anders
authors.initials: A
authors.lastname: Krogh
authors.affiliation: Department of Oncology, University of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen Ø, Denmark. katharina.anne.perell@regionh.dk.
authors.forename: Katharina
authors.initials: K
authors.lastname: Perell
authors.affiliation: Department of Radiology Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen Ø, Denmark. flemming.jensen@regionh.dk.
authors.forename: Flemming
authors.initials: F
authors.lastname: Jensen
authors.affiliation: Department of Oncology, University of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen Ø, Denmark. gedske.daugaard@regionh.dk.
authors.forename: Gedske
authors.initials: G
authors.lastname: Daugaard
authors.affiliation: Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100, Copenhagen Ø, Denmark. fcn@rh.dk.
authors.forename: Finn C
authors.initials: FC
authors.lastname: Nielsen
mesh_terms: D043171:Chromosomal Instability / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009382:Neoplasms, Unknown Primary / Q000145:classification / Q000235:genetics* / Q000473:pathology; D011379:Prognosis
chemical_list: D009363:Neoplasm Proteins