title: Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas.
abstract: Cytotoxic chemotherapy remains the main systemic therapy for gastro-oesophageal adenocarcinoma, but resistance to chemotherapy is common, resulting in ineffective and often toxic treatment for patients. Predictive biomarkers for chemotherapy response would increase the probability of successful therapy, but none are currently recommended for clinical use. We used global gene expression profiling of tumour biopsies to identify novel predictive biomarkers for cytotoxic chemotherapy.
  
  
  
  Tumour biopsies from patients (n=14) with TNM stage IB-IV gastro-oesophageal adenocarcinomas receiving platinum-based combination chemotherapy were used as a discovery cohort and profiled with Affymetrix ST1.0 Exon Genechips. An independent cohort of patients (n=154) treated with surgery with or without neoadjuvant platinum combination chemotherapy and gastric adenocarcinoma cell lines (n=22) were used for qualification of gene expression profiling results by immunohistochemistry. A cisplatin-resistant gastric cancer cell line, AGS Cis5, and the oesophageal adenocarcinoma cell line, OE33, were used for in vitro validation investigations.
  
  
  
  We identified 520 genes with differential expression (Mann-Whitney U, P<0.020) between radiological responding and nonresponding patients. Gene enrichment analysis (DAVID v6.7) was used on this list of 520 genes to identify pathways associated with response and identified the adipocytokine signalling pathway, with higher leptin mRNA associated with lack of radiological response (P=0.011). Similarly, in the independent cohort (n=154), higher leptin protein expression by immunohistochemistry in the tumour cells was associated with lack of histopathological response (P=0.007). Higher leptin protein expression by immunohistochemistry was also associated with improved survival in the absence of neoadjuvant chemotherapy, and patients with low leptin protein-expressing tumours had improved survival when treated by neoadjuvant chemotherapy (P for interaction=0.038). In the gastric adenocarcinoma cell lines, higher leptin protein expression was associated with resistance to cisplatin (P=0.008), but not to oxaliplatin (P=0.988) or 5fluorouracil (P=0.636). The leptin receptor antagonist SHLA increased the sensitivity of AGS Cis5 and OE33 cell lines to cisplatin.
  
  
  
  In gastro-oesophageal adenocarcinomas, tumour leptin expression is associated with chemoresistance but a better therapy-independent prognosis. Tumour leptin expression determined by immunohistochemistry has potential utility as a predictive marker of resistance to cytotoxic chemotherapy, and a prognostic marker independent of therapy in gastro-oesophageal adenocarcinoma. Leptin antagonists have been developed for clinical use and leptin and its associated pathways may also provide much needed novel therapeutic targets for gastro-oesophageal adenocarcinoma.
authors.affiliation: 1] Institute of Medical Sciences, School of Medicine and Dentistry, University of Aberdeen, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK [2] Department of Gastroenterology, Aberdeen Royal Infirmary, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK.
authors.forename: G H
authors.initials: GH
authors.lastname: Bain
authors.affiliation: Institute of Medical Sciences, School of Medicine and Dentistry, University of Aberdeen, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK.
authors.forename: E
authors.initials: E
authors.lastname: Collie-Duguid
authors.affiliation: 1] Institute of Medical Sciences, School of Medicine and Dentistry, University of Aberdeen, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK [2] Department of Pathology, Aberdeen Royal Infirmary, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK.
authors.forename: G I
authors.initials: GI
authors.lastname: Murray
authors.affiliation: Department of Radiology, Medical School, University of Cambridge, Cambridge CB2 0QQ, UK.
authors.forename: F J
authors.initials: FJ
authors.lastname: Gilbert
authors.affiliation: 1] Institute of Medical Sciences, School of Medicine and Dentistry, University of Aberdeen, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK [2] Department of Radiology, Aberdeen Royal Infirmary, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK [3] Department of Nuclear Medicine, Aberdeen Royal Infirmary, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK.
authors.forename: A
authors.initials: A
authors.lastname: Denison
authors.affiliation: Department of Nuclear Medicine, Aberdeen Royal Infirmary, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK.
authors.forename: F
authors.initials: F
authors.lastname: McKiddie
authors.affiliation: Department of Nuclear Medicine, Aberdeen Royal Infirmary, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK.
authors.forename: T
authors.initials: T
authors.lastname: Ahearn
authors.affiliation: Institute of Medical Sciences, School of Medicine and Dentistry, University of Aberdeen, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK.
authors.forename: I
authors.initials: I
authors.lastname: Fleming
authors.affiliation: Department of Gastroenterology, Aberdeen Royal Infirmary, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK.
authors.forename: J
authors.initials: J
authors.lastname: Leeds
authors.affiliation: Department of Gastroenterology, Aberdeen Royal Infirmary, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK.
authors.forename: P
authors.initials: P
authors.lastname: Phull
authors.affiliation: Department of Surgery, Aberdeen Royal Infirmary, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK.
authors.forename: K
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Surgery, Aberdeen Royal Infirmary, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK.
authors.forename: S
authors.initials: S
authors.lastname: Nanthakumaran
authors.forename: K M
authors.initials: KM
authors.lastname: Matula
authors.affiliation: Section of Pathology and Tumour Biology, Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds, UK.
authors.forename: H I
authors.initials: HI
authors.lastname: Grabsch
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: P
authors.initials: P
authors.lastname: Tan
authors.affiliation: Institute of Medical Sciences, School of Medicine and Dentistry, University of Aberdeen, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK.
authors.forename: A
authors.initials: A
authors.lastname: Welch
authors.affiliation: Institute of Medical Sciences, School of Medicine and Dentistry, University of Aberdeen, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK.
authors.forename: L
authors.initials: L
authors.lastname: Schweiger
authors.affiliation: 1] Institute of Medical Sciences, School of Medicine and Dentistry, University of Aberdeen, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK [2] Department of Oncology, Aberdeen Royal Infirmary, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK.
authors.forename: A
authors.initials: A
authors.lastname: Dahle-Smith
authors.affiliation: Institute of Medical Sciences, School of Medicine and Dentistry, University of Aberdeen, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK.
authors.forename: G
authors.initials: G
authors.lastname: Urquhart
authors.affiliation: Institute of Medical Sciences, School of Medicine and Dentistry, University of Aberdeen, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK.
authors.forename: M
authors.initials: M
authors.lastname: Finegan
authors.affiliation: 1] Institute of Medical Sciences, School of Medicine and Dentistry, University of Aberdeen, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK [2] Department of Oncology, Aberdeen Royal Infirmary, Foresterhill Health Campus, Foresterhill, Aberdeen, Scotland AB25 2ZN, UK.
authors.forename: R D
authors.initials: RD
authors.lastname: Petty
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D048708:Cell Growth Processes / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D020738:Leptin / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D020738:Leptin; D012333:RNA, Messenger