The cachexia syndrome represents a complex metabolic state accompanied by muscle wasting and a loss of body fat, hence quality of life is deteriorated and the prognosis of the patients who suffer from it is reduced 12. Reports mostly vary in the amount of weight loss (5–10%) and the time span (6–12 months) in which the weight loss occurs 34567. Up to one-half of untreated cancer patients is expected to lose weight while about one third is expected to lose more than 5%; about 20% of cancer deaths may be due to cachexia 3. Anorexia, defined as the loss of appetite and early satiety, is present in up to one-half of newly diagnosed cancer patients 8. In addition, a number of non-specific factors associated with cancer (e.g. changes in taste and smell, vomiting, pain) may contribute to limited food intake. However, loss of appetite is not obligatory for the development of cachexia 4.

Although a formal classification for cancer cachexia does not exist, it can be presumed that a variable interaction of tumour products, neuroendocrine changes, and host inflammatory molecules leads to this observable wasting 5. At present the mechanisms in the pathogenesis of cancer cachexia are still poorly understood. Here, the potential role of the melanocortin-4 receptor gene (MC4R) was investigated.

The MC4R is part of the leptinergic-melanocortinergic pathway that controls energy homeostasis. Stimulation of MC4R leads to higher energy expenditure, loss of appetite and weight loss 9. A series of experiments demonstrated that cancer cachexia is ameliorated by central MC4R blockade in MC4R knock out mice or by peripheral administration of an antagonist (e.g. agouti-related protein – AGRP) in rats, mice and sheep 910111213. Orally bioavailable potent antagonists of the human MC4R (e.g. synthesized compounds of Pyrrolidinones) demonstrated in vivo efficacy in protecting against cachectic symptoms in animal models of tumour-induced wasting and may be a suitable approach for the treatment of cachexia 1415.

In humans, mutations that reduce the function of the MC4R result in severe obesity 161718. The Val103Ile polymorphism is the most common MC4R variant, with allele frequencies > 1% in almost all studied populations 1719202122. This polymorphism was repeatedly shown to be negatively associated with above average weight and obesity in humans 212223. Recently, the initial finding (Geller et al., 2004) was replicated in an independent sample 24 comprising 5.603 individuals. Young et al. (2007) confirmed these findings in a meta-analysis comprising 29,563 individuals: individuals harbouring the Ile allele had an 18% lower risk of obesity compared with non-carriers 23. The Ile103 variant is assumed to entail a higher receptor activity 2425.

Our primary objective was to evaluate the role of the MC4R Val103Ile polymorphism in the development of cachexia in patients with cancer. We hypothesized that cancer patients with the 103Ile-allele of the MC4R are more likely to develop cancer cachexia than patients without the respective allele. Furthermore we analyzed if loss of appetite independent of therapy and thus disease-related, is associated with the 103Ile-allele.

The different malignant diseases that were diagnosed in our study group and the percentages of cachexia are shown in Table 1. Our results are consistent with previous reports that weight loss is more common in patients with lung and gastrointestinal cancer and less common in patients with breast cancer 335. Patients with malignant neoplasms according to ICD 10, including 14 patients with myelodysplastic syndromes (MDS) and six patients with myeloproliferative syndromes (MPD: polycythemia vera, essential thrombocythemia, osteomyelofibrosis) were included; these preleukaemic stages can transform into acute myeloic leukaemia. Most of the patients suffered from lymphoma, leukaemia and gastrointestinal tumours.

The average age in years (± SD) was 59.0 ± 14.5 (males: 58.8 ± 14.0, females 59.2 ± 14.0). Average BMI of all 509 patients one year before diagnosis of cancer was 26.0 ± 3.4 kg/m², at the time of diagnosis (prior to initiation of therapy) 25.5 ± 3.7 kg/m² and at ascertainment 25.3 ± 3.9 kg/m². 107 patients (21%) developed cancer cachexia (types 1–3, see Methods).

The Ile103 allele of the Val103Ile polymorphism of the MC4R gene has repeatedly been reported in several studies with a large number of cases and controls to be negatively associated with obesity and increased BMI 212223.

In the light of the postulated role of the MC4R in development of cachexia as determined in different rodent studies, we hypothesized that heterozygotes for the 103Ile allele are more prone to develop cancer cachexia. Surprisingly, our study did not provide any evidence for such an association (p = 0.13). Exploratory post-hoc analyses excluding patients with early leukaemic stages even revealed that there might be a trend towards the opposite effect (p < 0.05); heterozygotes for the 103Ile allele developed cancer cachexia less frequently in comparison to the rest of the study group. If this observation is not simply due to the usual problems of post-hoc subgroup analyses 36, one may speculate that there is a negative correlation between the Val103Ile polymorphism and cancer cachexia in patients with non-hematological/solid malignant neoplasms. This hypothesis has to be tested in additional studies.

If there is indeed a 'protective effect' conferred by the 103Ile allele that prevents patients with cancer from developing cachexia, it would be of interest to determine the underlying mechanisms. It is assumed that the Ile103 allele itself (or another variant in tight linkage disequilibrium) leads to a more active MC4R in functional terms 21. Since endogenous agonist binding properties and cell surface receptor expression levels are normal for this Val103Ile polymorphism, it had been difficult to link the Ile103 allele with a potential molecular effect. Recently, it was however, observed that the 103Ile MC4R showed a modest (2-fold) but statistically significant decrease in antagonist hAGRP(87–132) potency, which is consistent with a protective effect conferred by this variant 24. The effect of β-MSH, a potent agonist at the MC4R 25, seemed, on the other hand, to be increased for the 103Ile-allele 24. Hence, both, the lower antagonist and the increased agonist potencies are compatible with an elevated MC4R function, which could explain the weight reducing effect of the variant. However, these functional findings 232425, which are compatible with an elevated MC4R function, cannot explain the possible protection against the development of cachexia. There might be differences in binding of these or other endogenous ligands receptor-expression, in signal-transduction and/or physiological conditions 21.

Other explanations include: (i) There might be cachexia inducing factors that are produced by the tumour or resulting from host-tumour-interactions that preferentially react with the Ile103 variant. Deactivation or altered binding properties might ensue. This mechanism might lead to a reduced signalling of the MC4R expressing cells and thus result in an inborn resistance to the development of cancer cachexia. (ii) Alternatively, in the presence of cancer certain factors/conditions might alter the receptor, so that binding properties for an antagonist (e.g. AGRP) might improve. (iii) Acute-phase-protein-levels are elevated in patients developing cancer cachexia 37, possibly the interaction between one or a combination of these with the variant MC4R leads to the described effects.

To clarify if the risk of Ile103 carriers for development of cancer cachexia and potentially other forms of cachexia differs from wild type carriers, further studies in patients with solid tumors, and in comparison to non-solid malignant neoplasms are obviously warranted. Due to the carrier frequency in the range of 2–4% this evidently requires large and appropriately characterized patient samples.

Not surprisingly, an exploratory sub-group analysis revealed that changes of appetite (including loss of appetite in general, prior to initiation of therapy or during therapy and occurrence of both food craving and revulsion) might be associated with cancer cachexia (p < 0.01). This description is in line with previous studies 335. Interestingly, many patients could not concretize, some patients could not give any information pertaining to appetite pertaining to appetite; thus it was difficult to separate. We were especially interested in the patients with loss of appetite prior to initiation of therapy; 63.6% of these developed cachexia. However, loss of appetite does not seem to be necessary for developing cachexia, as already described in the past 4. Finally, we also obtained no evidence for an association of 103Ile carrier status and changes of appetite (p > 0.39).

In sum, our data do not support the hypothesis of a higher frequency of the 103Ile allele in patients developing cancer cachexia; contrariwise the frequency was descriptively higher in patients not developing cachexia. Thus, the role of the Val103Ile polymorphism of the MC4R for the development of cancer cachexia needs further clarification. Nevertheless, our data provide investigators with a basis to develop new hypotheses.

The author(s) declare that they have no competing interests.

SK, SZ and AH carried out the molecular genetic studies, participated in the sequence alignment, drafted the manuscript and participated in the design of the study. AS performed the statistical analysis. JH and AN conceived of the study, and participated in its design and coordination. All authors read and approved the final manuscript.