Treatment options for soft tissue sarcomas (STS) are often limited to surgery with the possibility of adjuvant chemotherapy and radiotherapy. The 5-year survival rate for STS patients is approximately 50% and depends strongly on the tumor stage . Therefore, it is necessary to develop new prognostic markers with the potential to estimate the efficacy of an individual therapeutic strategy.
STS are a heterogeneous group of relatively aggressive tumors probably originating from adult mesenchymal stem cells (hMSCs) [2–4]. A study regarding a subgroup of STS (malignant fibrous histiocytoma; MFH) described hMSCs as the progenitors of MFH. Furthermore, the authors reported a novel tumor suppression role for Wnt signaling in solid tumors, which may have the potential for a new therapeutic strategy in sarcomas .
Here, we investigated the prognostic impact of the stem cell marker, cancer-associated gene and Wnt/Tcf4 target gene LGR5/GPR49  in STS for the first time.
The leucine-rich repeat-containing G protein-coupled receptor LGR5/GPR49 has been identified as a novel stem cell marker in intestinal epithelia, stomach, and hair follicles [7–9]. Furthermore, LGR5/GPR49 mRNA was found to be expressed in normal human skeletal muscle tissues, which is of mesenchymal origin like STS .
LGR5/GPR49 mRNA is expressed in basal cell carcinoma (tumor of hair follicle), colorectal cancer and in tumors of the colon, ovary and liver [10–13]. Investigations of the LGR5/GPR49 protein expression are rare [14, 15] because a full accepted antibody against LGR5/GPR49 is not available at the moment [6, 16]. However, a prognostic impact of LGR5/GPR49 has not been shown so far.
The function of LGR5/GPR49 in tumorigenesis is supported by its ability to induce transformation of NIH3T3 cells in the presence of conditioned media from colorectal tumor cells. These findings indicate the possibility that the ligand of LGR5/GPR49 could be secreted by tumor cells . McClanahan and colleagues therefore suggest a role for LGR5/GPR49 as a member of a novel class of transforming oncogenes and, as a result, a new potential molecular target for therapeutic intervention .
To our knowledge only one transcript variant of LGR5/GPR49, which lacks exon 8, is published in the ExPASy UniProtKB-data bank as variant VSP_037746 http://www.uniprot.org/uniprot/O75473. In this study, we identified a novel transcript variant of LGR5/GPR49 that lacks exon 5 (GPR49Δ5) (listed by us in the EMBL-Bank; http://www.ebi.ac.uk/ena/data/view/FN820440).
These variants are very interesting because both published LGR5/GPR49 variants have a truncated ligand binding extracellular domain [6, 10]. It is possible that the affinity of these variants to the recently identified ligand of the full length LGR5/GPR49 gene product  is different or that different ligands could bind to the shortened receptor.
In summary, we report the first results for a newly identified variant of the LGR5/GPR49 gene, lacking exon 5, that we call GPR49Δ5. This is the first study that has demonstrated a prognostic impact of a LGR5/GPR49 variant in STS. In a multivariate Cox's regression analysis, we found that a low GPR49Δ5 mRNA level is an independent negative prognostic marker for disease-associated survival as well as for recurrence-free survival in STS patients.