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Using transcriptomics to identify and validate novel biomarkers of human skeletal muscle cancer cachexia

Nathan A Stephens1, Iain J Gallagher2*, Olav Rooyackers3, Richard J Skipworth1, Ben H Tan1, Troels Marstrand4, James A Ross1, Denis C Guttridge5, Lars Lundell3, Kenneth C Fearon1 and James A Timmons267*

Author Affiliations

1 Department of Clinical and Surgical Sciences (Surgery), School of Clinical Sciences and Community Health, University of Edinburgh, EH16 4SB, UK

2 Translational Biomedicine, Heriot-Watt University, Edinburgh, EH14 4AS, UK

3 Department of Anaesthesiology and Intensive Care, and Department of Surgery, Karolinska University Hospital, 14186, Huddinge, Sweden

4 Department of Biology and Biotech Research and Innovation Centre, Ole Maaloes Vej 5, University of Copenhagen, DK-2200, Denmark

5 Division of Human Cancer Genetics, Ohio State University Medical Center, Columbus, OH 43210, USA

6 Lifestyle Research Group, The Royal Veterinary College, 4 Royal College Street, University of London, NW1 0TU, UK

7 Centre for Healthy Ageing, Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej, DK-2200, Denmark

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Genome Medicine 2010, 2:1  doi:10.1186/gm122

Published: 15 January 2010

Abstract

Background

Cancer cachexia is a multi-organ tissue wasting syndrome that contributes to morbidity and mortality in many cancer patients. Skeletal muscle loss represents an established key feature yet there is no molecular understanding of the disease process. In fact, the postulated molecular regulators of cancer cachexia originate largely from pre-clinical models and it is unclear how these translate to the clinical environment.

Methods

Rectus abdominis muscle biopsies were obtained from 65 upper gastrointestinal (UGI) cancer patients during open surgery and RNA profiling was performed on a subset of this cohort (n = 21) using the Affymetrix U133+2 platform. Quantitative analysis revealed a gene signature, which underwent technical validation and independent confirmation in a separate clinical cohort.

Results

Quantitative significance analysis of microarrays produced an 83-gene signature that was able to identify patients with greater than 5% weight loss, while this molecular profile was unrelated to markers of systemic inflammation. Selected genes correlating with weight loss were validated using quantitative real-time PCR and independently studied as general cachexia biomarkers in diaphragm and vastus lateralis from a second cohort (n = 13; UGI cancer patients). CaMKIIβ correlated positively with weight loss in all muscle groups and CaMKII protein levels were elevated in rectus abdominis. TIE1 was also positively associated with weight loss in both rectus abdominis and vastus lateralis muscle groups while other biomarkers demonstrated tissue-specific expression patterns. Candidates selected from the pre-clinical literature, including FOXO protein and ubiquitin E3 ligases, were not related to weight loss in this human clinical study. Furthermore, promoter analysis identified that the 83 weight loss-associated genes had fewer FOXO binding sites than expected by chance.

Conclusion

We were able to discover and validate new molecular biomarkers of human cancer cachexia. The exercise activated genes CaMKIIβ and TIE1 related positively to weight-loss across muscle groups, indicating that this cachexia signature is not simply due to patient inactivity. Indeed, excessive CaMKIIβ activation is a potential mechanism for reduced muscle protein synthesis. Our genomics analysis also supports the view that the available preclinical models do not accurately reflect the molecular characteristics of human muscle from cancer cachexia patients.