title: Variations in genes involved in dormancy associated with outcome in patients with resected colorectal liver metastases.
abstract: BACKGROUND
  Tumor dormancy has been described as a state of hibernation. Dormancy can be switched to proliferation by different pathways, which may play a critical role in tumor recurrence. In this study, we investigated genetic variations within genes involved in tumor dormancy and their association with recurrence and outcome in patients with colorectal liver metastases (CLM) who underwent neoadjuvant bevacizumab-based chemotherapy.
  
  
  METHODS
  Genomic DNA was extracted from resected CLM (FFPE) from 149 patients. Single-nucleotide polymorphisms (SNPs) in 14 genes associated with dormancy were analyzed by direct Sanger DNA sequencing and evaluated for response, recurrence-free survival (RFS), overall survival (OS) and recurrence patterns.
  
  
  RESULTS
  NME1 rs34214448 C>A was significantly associated with RFS in univariable analysis (P = 0.039) and with intrahepatic recurrence (P = 0.014). NOTCH3 rs1044009 T>C and CD44 rs8193 C>T showed a significant difference in 3-year OS rates (P = 0.004 and P = 0.042, respectively). With respect to radiological response, CD44 rs8193 C>T variant genotypes were associated with a significantly higher response rate (P = 0.033). Recursive partitioning analyses revealed that Dll4 rs12441495 C>G, NME1 rs34214448 C>A and NOTCH3 rs1044009 T>C were the dominant SNPs predicting histological response, RFS and OS, respectively.
  
  
  CONCLUSIONS
  Our data suggest that gene variations within genes involved in tumor dormancy pathways are associated with response and outcome in patients with resected CLM. These data may lead to new and more effective treatment strategies targeting tumor dormancy.
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA Department of Surgery, Medical University Vienna, Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Stremitzer
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
authors.forename: D
authors.initials: D
authors.lastname: Yang
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ning
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
authors.forename: S
authors.initials: S
authors.lastname: Stintzing
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Sunakawa
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sebio
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
authors.forename: S
authors.initials: S
authors.lastname: Yamauchi
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
authors.forename: S
authors.initials: S
authors.lastname: Matsusaka
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
authors.forename: A
authors.initials: A
authors.lastname: Parekh
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
authors.forename: A
authors.initials: A
authors.lastname: Barzi
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
authors.forename: R
authors.initials: R
authors.lastname: El-Khoueiry
authors.affiliation: Clinical Institute of Pathology, Medical University Vienna, Vienna.
authors.forename: J
authors.initials: J
authors.lastname: Stift
authors.affiliation: Clinical Institute of Pathology, Medical University Vienna, Vienna.
authors.forename: F
authors.initials: F
authors.lastname: Wrba
authors.affiliation: Department of Surgery I, Rudolfstiftung Hospital, Vienna, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Gruenberger
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA lenz@usc.edu.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002135:Calcium-Binding Proteins; D002277:Carcinoma / Q000235:genetics* / Q000556:secondary / Q000601:surgery; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D016208:Databases, Factual; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000556:secondary / Q000601:surgery; D008297:Male; D059146:Metastasectomy; D008875:Middle Aged; D054778:NM23 Nucleoside Diphosphate Kinases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C497483:CD44 protein, human; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D018960:Hyaluronan Receptors; D036341:Intercellular Signaling Peptides and Proteins; D054778:NM23 Nucleoside Diphosphate Kinases; C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch; C517938:NME1 protein, human
keywords: bevacizumab; colorectal liver metastases; dormancy; neoadjuvant chemotherapy; single-nucleotide polymorphisms