P‐selectin genotype is associated with the development of cancer cachexia

Benjamin H L Tan,Daniel L Marks,D A Christopher Deans,Florian Strasser,Stein Kaasa,Kenneth C H Fearon,Tora S Solheim,James A Ross,Antonio Vigano,Frank Skorpen,Richard J E Skipworth,Sambasivarao Damaraju,Torill Fladvad,Vickie E Baracos,Theodore P Braun,European Palliative Care Research Collaborative

doi:10.1002/emmm.201200231

Abstract

The variable predisposition to cachexia may, in part, be due to the interaction of host genotype. We analyzed 129 single nucleotide polymorphisms (SNPs) in 80 genes for association with cachexia based on degree of weight loss (>5, >10, >15%) as well as weight loss in the presence of systemic inflammation (C-reactive protein, >10 mg/l). 775 cancer patients were studied with a validation association study performed on an independently recruited cohort (n = 101) of cancer patients. The C allele (minor allele frequency 10.7%) of the rs6136 (SELP) SNP was found to be associated with weight loss >10% both in the discovery study (odds ratio (OR) 0.52; 95% confidence intervals (CI), 0.29–0.93; p = 0.026) and the validation study (OR 0.09, 95% CI 0.01–0.98, p = 0.035). In separate studies, induction of muscle atrophy gene expression was investigated using qPCR following either tumour-induced cachexia in rats or intra-peritoneal injection of lipopolysaccharide in mice. P-selectin was found to be significantly upregulated in muscle in both models. Identification of P-selectin as relevant in both animal models and in cachectic cancer patients supports this as a risk factor/potential mediator in cachexia.

Highlights

The variable predisposition to cachexia may, in part, be due to the interaction of host genotype
The C allele of the rs6136 (SELP) single nucleotide polymorphism (SNP) was found to be associated with weight loss >10% both in the discovery study (odds ratio (OR) 0.52; 95% confidence intervals (CI), 0.29–0.93; p 1⁄4 0.026) and the validation study
Identification of P-selectin as relevant in both animal models and in cachectic cancer patients supports this as a risk factor/potential mediator in cachexia

Summary

Introduction

The variable predisposition to cachexia may, in part, be due to the interaction of host genotype. EMBO Mol Med 4, 462–471 www.embomolmed.org patients, who will develop cancer cachexia and who will not Such variation may, in part, be due to the patient’s genotype. The wealth of known genetic polymorphisms in genes controlling pro/antiinflammatory pathways, neuronal melanocortin signalling pathways and muscle and adipose tissue catabolic pathways suggest their exploitable potential as biomarkers of interindividual predictability of developing cachexia. We utilized a candidate gene approach to evaluate the association between genetic polymorphisms and the risks of developing cachexia in patients recruited across three centres. To further corroborate the most significantly related single nucleotide polymorphism (SNP) to cancer cachexia in the gene association study, we tested the same gene for participation in the induction of the skeletal muscle atrophy gene program, either by intra-peritoneal administration of lipopolysaccharide (LPS) in mice or in a rat model of cancer cachexia (methylcholanthrene (MCA)-induced sarcoma). The MCA model is a preclinical cancer cachexia model, and is known to reliably induce loss of lean body mass (Sato et al, 2001)

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Results

Conclusion