Abstract 590: Identification and validation of novel candidate circulating biomarkers in high-grade soft tissue sarcoma

Abstract

Abstract Soft Tissue Sarcoma (STS) are rare mesenchymal tumors, accounting for less than 1% of adult and 7-10% of pediatric cancers respectively. They are very complex and approximately include 50 different benign and malignant histotypes. Identification of circulating cancer biomarkers improves early detection and is important in determining patient risk stratification, in monitoring tumor progression and therapy response, and in planning new treatment. However, at present there are no laboratory tests that allow reliable early STS diagnosis and consequent prognosis. Discovery of new serum protein biomarkers is especially needed for patients with advanced/metastatic STS for whom the outcome remains strongly unfavorable. Proteomic technologies are used for global profiling and identification of disease-associated markers in biological fluids, such as serum. The low-molecular-weight (LMW) proteome (<30 kDa) is considered a rich source of new potential biomarkers, that are often masked by the presence of abundant proteins in serum. In order to determine whether low-abundant serum proteins/peptides can be indicative of advanced disease, we analyzed 53 high-grade STS sera divided in discovery (34 sera) and validation (19 sera) subsets by using poly(N-isopropylacrylamide-co-vinylsulfonic acid) hydrogel core-shell nanoparticles with incorporated Cibacron Blue F3G-A. These nanoparticles selectively entrap LMW proteins/peptides on the bases of size exclusion and affinity chromatography. These nanoparticles protect the analytes from enzymatic degradation and amplify the concentration for mass spectrometry detection. 13 benign STS and 20 healthy sera were used as control. The most significant protein, IGFBP7, was then validated in a wider series of cases including 59 high-grade STS sera by ELISA assay and 86 paraffin-embedded high-grade primary STS by immunohistochemistry. Mass spectrometry data revealed 17 proteins/peptides common to discovery and validation subsets with significance differences in abundance when compared to benign and/or normal sera. The function of selected biomarkers was predominantly related to calcium-binding proteins (MGP), immune response (Ceruloplasmin, Lactotransferrin), coagulation process (Serpin C1) and metabolism (TGFBI). Moreover, as confirmed by ELISA assay, expression of insulin-like growth factor binding protein 7 (IGFBP7) involved in cell signaling pathway progressively increased in healthy, benign and malignant tumors. With immunohistochemistry, tissue IGFBP7 had a significantly higher expression in metastatic than in non metastatic STS. Our data suggest that proteomic technology is able to identify circulating biomarkers associated to STS malignant phenotype and IGFBP7 in paired primary specimens may discriminate STS patients with increased risk of metastatic progression. Citation Format: Amalia Conti, Claudia Fredolini, Davide Tamburro, Giovanna Magagnoli, Weidong Zhou, Lance A. Liotta, Piero Picci, Alessandra Luchini, Maria Serena Benassi. Identification and validation of novel candidate circulating biomarkers in high-grade soft tissue sarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 590. doi:10.1158/1538-7445.AM2015-590