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A novel splice variant of the stem cell marker LGR5/GPR49 is correlated with the risk of tumor-related death in soft-tissue sarcoma patients.

ABSTRACT: BACKGROUND: The human leucine-rich, repeat-containing G protein-coupled receptor (LGR) 5, also called GPR49, is a marker of stem cells in adult intestinal epithelium, stomach and hair follicles. LGR5/GPR49 is overexpressed in tumors of the colon, ovary and liver and in basal cell carcinomas. Moreover, an expression in skeletal muscle tissues was also detected. However, there has been no investigation regarding the expression and function of LGR5/GPR49 in soft-tissue sarcomas (STS) yet. METHODS: Seventy-seven frozen tumor samples from adult STS patients were studied using quantitative real-time TaqMan™ PCR analysis. The mRNA levels of wild type LGR5/GPR49 and a newly identified splice variant of LGR5/GPR49 lacking exon 5 (that we called GPR49?5) were quantified. RESULTS: A low mRNA expression level of GPR49?5, but not wild type LGR5/GPR49, was significantly correlated with a poor prognosis for the disease-associated survival of STS patients (RR = 2.6; P = 0.026; multivariate Cox's regression hazard analysis). Furthermore, a low mRNA expression level of GPR49?5 was associated with a shorter recurrence-free survival (P = 0.043). However, tumor onset in patients with a lower expression level of GPR49?5 mRNA occurred 7.5 years later (P = 0.04) than in patients with a higher tumor level of GPR49?5 mRNA. CONCLUSION: An attenuated mRNA level of the newly identified transcript variant GPR49?5 is a negative prognostic marker for disease-associated and recurrence-free survival in STS patients. Additionally, a lower GPR49?5 mRNA level is associated with a later age of tumor onset. A putative role of GPR49?5 expression in tumorigenesis and tumor progression of soft tissue sarcomas is suggested.

SUBMITTER: Rot S

PROVIDER: S-EPMC3203099 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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A novel splice variant of the stem cell marker LGR5/GPR49 is correlated with the risk of tumor-related death in soft-tissue sarcoma patients.

Rot Swetlana S Taubert Helge H Bache Matthias M Greither Thomas T Würl Peter P Eckert Alexander W AW Schubert Johannes J Vordermark Dirk D Kappler Matthias M

BMC cancer 20111006

<h4>Background</h4>The human leucine-rich, repeat-containing G protein-coupled receptor (LGR) 5, also called GPR49, is a marker of stem cells in adult intestinal epithelium, stomach and hair follicles. LGR5/GPR49 is overexpressed in tumors of the colon, ovary and liver and in basal cell carcinomas. Moreover, an expression in skeletal muscle tissues was also detected. However, there has been no investigation regarding the expression and function of LGR5/GPR49 in soft-tissue sarcomas (STS) yet.<h4 ...[more]

PMID: 21978106

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Project description:High-grade soft-tissue sarcoma (STS) is a highly malignant neoplasm with a poor overall prognosis. Numerous prognostic factors determine tumor progression and patient outcomes. Various immune-associated cells identified in the tumor microenvironment have important roles in various tumor types. The present study was performed to evaluate the expression of immune-associated genes and to elucidate the association between these genes and the prognosis in high-grade STS. A total of 12 formalin-fixed, paraffin-embedded tissue samples of high-grade STS were subjected to gene expression analysis using the NanoString nCounter® System and another 35 samples were used for immunohistochemistry. For comparative analysis, the patients were divided into two groups according to overall survival (OS). The expression levels of 770 genes were first analyzed using the nCounter® PanCancer Immune Profiling Panel. Immunohistochemistry was then performed for the most significantly altered genes. Subsequently, the association between gene expression and prognosis of high-grade STS was evaluated. Of the 770 immune-associated genes analyzed, several genes were identified as being differentially expressed between the two groups. Based on gene expression levels and fold change, 13 representative genes were identified; 7 of the 13 candidate genes (C3, CD36, DOCK9, FCER2, FOS, HLA-DRB4 and NCAM1) were significantly overexpressed in the poor prognosis group, while the other 6 immune-associated genes (BIRC5, DUSP4, FOXP3, HLA-DQA1, HLA-DQB1 and LAG3) were increased in the good prognosis group. By immunohistochemistry, the expression of the 13 immune-associated genes was confirmed to be significantly different between the two groups. Expression of HLA-DQA1, HLA-DQB1 and HLA-DRB4 was observed in 74.3, 34.3 and 48.6% of tumors, respectively. HLA-DQA1 and HLA-DQB1 were significantly decreased, whereas HLA-DRB4 was significantly increased in the poor prognosis group. Of note, expression of HLA-DQA1 was associated with a significantly longer OS (P=0.028). In conclusion, HLA-DQA1 expression was significantly associated with long-term survival and may therefore be an immune biomarker for good prognosis in high-grade STS.

Dataset Information

A novel splice variant of the stem cell marker LGR5/GPR49 is correlated with the risk of tumor-related death in soft-tissue sarcoma patients.

Publications

A novel splice variant of the stem cell marker LGR5/GPR49 is correlated with the risk of tumor-related death in soft-tissue sarcoma patients.

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