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Evaluating potential biomarkers of cachexia and survival in skeletal muscle of upper gastrointestinal cancer patients

Citation
Stephens N, Skipworth RJE, Gallagher IJ, Greig C, Guttridge DC, Ross JA & Fearon KCH (2015) Evaluating potential biomarkers of cachexia and survival in skeletal muscle of upper gastrointestinal cancer patients, Journal of Cachexia, Sarcopenia and Muscle, 6 (1), pp. 53-61.

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. {\textgreater}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.

Keywords
Biomarkers; Cachexia; Cancer; Skeletal muscle; Survival

StatusPublished
AuthorsStephens Nathan, Skipworth Richard J E, Gallagher Iain J, Greig Carolyn, Guttridge Denis C, Ross James A, Fearon Kenneth C H
Publication date03/2015
Publication date online31/03/2015
Date accepted by journal10/09/2014
PublisherWiley-Blackwell
ISSN 2190-5991
LanguageEnglish

Journal
Journal of Cachexia, Sarcopenia and Muscle: Volume 6, Issue 1 (2015)

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