title: TOP1 gene copy numbers are increased in cancers of the bile duct and pancreas.
abstract: BACKGROUND
  Bile duct and pancreatic cancer (PC) have poor prognoses and treatment options for inoperable patients are scarce. In order to improve outcome for these patients, there is an urgent need for biomarkers predictive of treatment effect. Irinotecan is a topoisomerase 1 (Top1) poison. Top1 protein, TOP1 gene copy number and mRNA expression, respectively, have been proposed as predictive biomarkers of response to irinotecan in other cancers. Here we investigate the occurrence of TOP1 gene aberrations in cancers of the bile ducts and pancreas.
  
  
  METHODS
  TOP1 and centromere 20 (CEN-20) numbers were investigated by fluorescence in situ hybridization analyses in tumor tissue from 226 patients. The frequencies of aberration in the TOP1 gene copy number, the CEN-20 copy number and the TOP1/CEN-20 ratio were analyzed. As TOP1 is located on chromosome 20, the CEN-20 probe was included to distinguish between chromosomal and gene amplifications.
  
  
  RESULTS
  In PC, 29.8% had an increased TOP1 copy number (≥ 3.5n gene copies per cell) and 10.8% had a TOP1/CEN-20 ratio >1.5. In bile duct cancer, 12.8 % had an increased TOP1 copy number and 6.4% had a TOP1/CEN-20 ratio >1.5. Neither the TOP1 copy number nor the TOP1/CEN-20 ratios could predict overall survival.
  
  
  CONCLUSIONS
  We here report that a substantial number of patients with bile duct or PC have increased TOP1 copy number and increased TOP1/CEN-20 ratio making further analyses on the association between TOP1 gene copy number and irinotecan efficacy clinically relevant.
authors.affiliation: Deptartment of Oncology, Rigshospitalet, Copenhagen University Hospital , Copenhagen , Denmark.
authors.forename: Mie
authors.initials: M
authors.lastname: Grunnet
authors.forename: Dan
authors.initials: D
authors.lastname: Calatayud
authors.forename: Nicolai A A
authors.initials: NA
authors.lastname: Schultz
authors.forename: Jane P
authors.initials: JP
authors.lastname: Hasselby
authors.forename: Morten
authors.initials: M
authors.lastname: Mau-Sørensen
authors.forename: Nils
authors.initials: N
authors.lastname: Brünner
authors.forename: Jan
authors.initials: J
authors.lastname: Stenvang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D001650:Bile Duct Neoplasms / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics; D002503:Centromere; D002890:Chromosomes, Human, Pair 20; D004264:DNA Topoisomerases, Type I / Q000235:genetics*; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D010190:Pancreatic Neoplasms / Q000235:genetics*; D011003:Ploidies; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human
keywords: bile duct cancer; biomarkers; pancreatic cancer; prediction; topoisomerase-1