title: Evaluating potential biomarkers of cachexia and survival in skeletal muscle of upper gastrointestinal cancer patients.
abstract: BACKGROUND
  In order to grow the potential therapeutic armamentarium in the cachexia domain of supportive oncology, there is a pressing need to develop suitable biomarkers and potential drug targets. This pilot study evaluated several potential candidate biomarkers in skeletal muscle biopsies from a cohort of upper gastrointestinal cancer (UGIC) patients.
  
  
  METHODS
  One hundred seven patients (15 weight-stable healthy controls (HC) and 92 UGIC patients) were recruited. Mean (standard deviation) weight-loss of UGIC patients was 8.1 (9.3%). Cachexia was defined as weight-loss ≥5%. Rectus abdominis muscle was obtained at surgery and was analysed by western blotting or quantitative real-time-polymerase chain reaction. Candidate markers were selected according to previous literature and included Akt and phosphorylated Akt (pAkt, n = 52), forkhead box O transcription factors (n = 59), ubiquitin E3 ligases (n = 59, control of muscle anabolism/catabolism), BNIP3 and GABARAPL1 (n = 59, as markers of autophagy), myosin heavy-chain (MyHC, n = 54), dystrophin (n = 39), β-dystroglycan (n = 52), and β-sarcoglycan (n = 52, as markers of structural alteration in a muscle). Patients were followed up for an average of 1255 days (range 581-1955 days) or until death. Patients were grouped accordingly and analysed by (i) all cancer patients vs. HC; (ii) cachectic vs. non-cachectic cancer patients; and (iii) cancer patients surviving ≤1 vs. >1 year post operatively.
  
  
  RESULTS
  Cancer compared with HC patients had reduced mean (standard deviation) total Akt protein [0.49 (0.31) vs. 0.89 (0.17), P = 0.001], increased ratio of phosphorylated to total Akt [1.33 (1.04) vs. 0.32 (0.21), P = 0.002] and increased expression of GABARAPL1 [1.60 (0.76) vs. 1.10 (0.57), P = 0.024]. β-Dystroglycan levels were higher in cachectic compared with non-cachectic cancer patients [1.01 (0.16) vs. 0.87 (0.20), P = 0.007]. Survival was shortened in patients with low compared with high MyHC levels (median 316 vs. 1326 days, P = 0.023) and dystrophin levels (median 341 vs. 660 days, P = 0.008).
  
  
  CONCLUSIONS
  The present study has identified intramuscular protein level of β-dystroglycan as a potential biomarker of cancer cachexia. Changes in the structural elements of muscle (MyHC or dystrophin) appear to be survival biomarkers.
authors.affiliation: Department of Clinical and Surgical Sciences (Surgery), School of Clinical Sciences, University of Edinburgh, Royal Infirmary, 51 Little France Crescent, Edinburgh, EH16 4SA, UK.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Stephens
authors.affiliation: Department of Clinical and Surgical Sciences (Surgery), School of Clinical Sciences, University of Edinburgh, Royal Infirmary, 51 Little France Crescent, Edinburgh, EH16 4SA, UK.
authors.forename: Richard J E
authors.initials: RJ
authors.lastname: Skipworth
authors.affiliation: Department of Clinical and Surgical Sciences (Surgery), School of Clinical Sciences, University of Edinburgh, Royal Infirmary, 51 Little France Crescent, Edinburgh, EH16 4SA, UK.
authors.forename: Iain J
authors.initials: IJ
authors.lastname: Gallagher
authors.affiliation: Department of Clinical and Surgical Sciences (Surgery), School of Clinical Sciences, University of Edinburgh, Royal Infirmary, 51 Little France Crescent, Edinburgh, EH16 4SA, UK.
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Greig
authors.affiliation: Division of Human Cancer Genetics, The Ohio State University Wexner Medical Center, 410 W. 10th Ave., Columbus, OH, 43210, USA.
authors.forename: Denis C
authors.initials: DC
authors.lastname: Guttridge
authors.affiliation: Department of Clinical and Surgical Sciences (Surgery), School of Clinical Sciences, University of Edinburgh, Royal Infirmary, 51 Little France Crescent, Edinburgh, EH16 4SA, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Ross
authors.affiliation: Department of Clinical and Surgical Sciences (Surgery), School of Clinical Sciences, University of Edinburgh, Royal Infirmary, 51 Little France Crescent, Edinburgh, EH16 4SA, UK.
authors.forename: Kenneth C H
authors.initials: KC
authors.lastname: Fearon
keywords: Biomarkers; Cachexia; Cancer; Skeletal muscle; Survival