IGF2 over-expression in solitary fibrous tumours is independent of anatomical location and is related to loss of imprinting

Abstract

Solitary fibrous tumour (SFT) is a mesenchymal neoplasm composed of CD34-positive fibroblastic cells. The pathogenesis driving this neoplasm remains unclear, with no recurrent genetic aberrations described to date. Previous reports suggest a role for IGF2 over-expression in the pathogenesis of these tumours, implicated in triggering hypoglycaemia in some patients. The expression profiling of 23 SFTs was investigated using an Affymetrix U133A platform. The transcriptional signature was compared to a set of 34 soft tissue sarcomas spanning seven subtypes. Potential candidate genes were then further investigated for activating mutations or loss of imprinting (LOI). SFT had a distinct expression signature and clustered in a tight genomic cluster, separate from all other sarcoma subtypes. A number of over-expressed receptor tyrosine kinase (RTK) genes were identified in SFT, including DDR1, ERBB2 and FGFR1; however, no mutations were identified by cDNA sequencing. Over-expression of IGF2 was uniformly detected in SFT, regardless of anatomical location, and was related to LOI. In contrast, IGF1 and JUN over-expression was seen in pleural, but not meningeal, locations. SFT shows a distinctive expression signature, with over-expression of DDR1, ERBB2 and FGFR1. Despite of lack of activating mutations in these RTKs, therapy with specific inhibitors targeting these kinases might be considered in advanced/metastatic cases. Our results confirm LOI in several tumours expressing high levels of IGF2, which may explain the observed paraneoplastic hypoglycaemia.

Fig 1

Hierarchical unsupervised clustering was performed using Partek^® Genomics Suite™ across all genes present on the Affymetrix U133A chip: A) a tight SFT genomic cluster separate from all other sarcoma types was observed; B) primary location did not appear to influence clustering. Note that samples: SFT28 and SFT32 were obtained from the same patient.

Fig. 2

Distribution of mRNA expression based on different anatomic locations of SFT: A-C: including genes involved in IGF pathway, such as IGF2, INSR and IGF1; and D. DDR1 expression.

Fig. 3

Diagram of IGF/INSR/IGF1R signaling pathway.