title: Alternative lengthening of telomeres predicts site of origin in neuroendocrine tumor liver metastases.
abstract: BACKGROUND
  The determination of the primary tumor origin in patients with neuroendocrine tumor liver metastases (NELM) can pose a considerable management challenge. Recent studies have shown that the alternative lengthening of telomeres (ALT) is prevalent in some human tumors, including pancreatic neuroendocrine tumors (PanNET), and can be useful in predicting tumor biology. In this study, we aimed to evaluate the use of ALT as a biomarker in patients with NELM, in particular to predict the site of origin of metastases.
  
  
  METHODS
  Tissue microarrays (TMAs) were constructed using tumor tissue from NELM patients undergoing liver resection between 1998 and 2010. These included 43 PanNET and 47 gastrointestinal carcinoid tumors. The TMAs were tested for ALT using telomere-specific fluorescent in situ hybridization. The association between ALT positivity and clinicopathologic features and long-term outcomes was investigated.
  
  
  RESULTS
  Alternative lengthening of telomeres was positive (ALT+) in 26 (29%) of the 90 tumors included in the TMAs. Pancreatic neuroendocrine tumors were ALT+ in 56% of patients, compared with only 4% ALT+ among gastrointestinal carcinoid tumors (p < 0.001). The specificity of ALT for detecting pancreatic origin was 96% and the positive predictive value was 92%, and sensitivity was 56% and the negative predictive value was 70%. Additionally, ALT was associated with the pattern of metastatic disease: ALT+ NELM were more likely to have oligometastases (p = 0.001) and less likely to be bilateral in distribution (p = 0.05) than were ALT tumors. In addition, ALT+ was associated with improved prognosis in the PanNET patient population.
  
  
  CONCLUSIONS
  Alternative lengthening of telomeres was found to be a useful biomarker in patients with NELM. This marker can be helpful in guiding therapy by identifying the site of origin in patients in whom the primary site is unknown.
authors.affiliation: Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD.
authors.forename: Epameinondas
authors.initials: E
authors.lastname: Dogeas
authors.affiliation: Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD.
authors.forename: Georgios
authors.initials: G
authors.lastname: Karagkounis
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Heaphy
authors.affiliation: Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Hirose
authors.affiliation: Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Pawlik
authors.affiliation: Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Wolfgang
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD.
authors.forename: Alan
authors.initials: A
authors.lastname: Meeker
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD.
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.affiliation: Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD.
authors.forename: John L
authors.initials: JL
authors.lastname: Cameron
authors.affiliation: Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD; Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX. Electronic address: michael.choti@utsouthwestern.edu.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Choti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000473:pathology*; D005819:Genetic Markers; D006498:Hepatectomy; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008113:Liver Neoplasms / Q000235:genetics / Q000401:mortality / Q000556:secondary* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000401:mortality / Q000556:secondary* / Q000601:surgery; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D011237:Predictive Value of Tests; D011379:Prognosis; D012680:Sensitivity and Specificity; D016037:Single-Blind Method; D016019:Survival Analysis; D016615:Telomere / Q000473:pathology*; D059505:Telomere Homeostasis; D046888:Tissue Array Analysis; D055815:Young Adult
chemical_list: D005819:Genetic Markers