Abstract 3490: IGF2BP3 (IMP3) expression is associated with worse survival in well-differentiated/dedifferentiated (WD/DD) liposarcoma

Abstract Background: Liposarcoma (LPS) is an understudied form of soft tissue sarcoma (STS). The well-differentiated (WD) and de-differentiated (DD) subtypes of LPS are associated with indolent and aggressive disease courses, respectively, but this histologic stratification fails to fully capture disease heterogeneity. Molecular approaches may help refine prognostication and inform treatment intensification. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3 or IMP3), is an RNA-binding protein that regulates gene expression by controlling mRNA stability and has been implicated in tumorigenesis and poor prognosis in many cancers. We hypothesized IGF2BP3 would refine the prognostication of LPS beyond its WD/DD histologic status. Methods: We examined the association between IGF2BP3 gene or protein expression and clinical data in four datasets: (1) patients with STS subtypes (n=206) in the cancer genome atlas (TCGA) database, (2) an in-house gene microarray of lipomatous tumors (n=71), LPS cell lines (n=3) and patient-derived xenografts (PDX, n=3), (3) an in-house tissue microarray (TMA) of lipomatous tumors (n=115), LPS cell lines (n=3) and PDXs (n=3) and (4) an in-house TMA of WD/DD LPS (n=71). IGF2BP3 protein expression in TMAs was quantified by immunohistochemistry (IHC). IGF2BP3 gene and protein expression values from identical samples were compared by Pearson correlation (n=43). The Kaplan-Meier method and log-rank test were used to compare survival outcomes. Results: In the TCGA cohort, which does not include WD LPS, IGF2BP3 expression was a poor prognostic factor solely in DD LPS (n=50, median overall survival (mOS): 1.6 vs 5.0 years, p=0.009). Among gene microarray samples, IGF2BP3 expression was highest in DD LPS (n=18) compared to WD LPS (n=29) and lipoma (n=7) by paired t-tests (p=0.03 and 0.002, respectively) and IGF2BP3 expression was associated with worse survival in WD/DD LPS (mOS 7.7 vs 21.5 years, p=0.02). In both TMAs, IGF2BP3 expression (>25% cell positivity/core) portended worse survival in WD/DD LPS (mOS (3): 3.7 vs 13.8 years, p<0.001 and mOS (4): 2.7 vs 14.9 years, p<0.001). IGF2BP3 was not expressed in myxoid LPS (n=21) or lipoma (n=8) samples. Gene and protein expression of IGF2BP3 were positively correlated in WD/DD LPS (r2 = 0.69). IGF2BP3 expression was more strongly associated with survival than LPS differentiation status (mOS: 7.0 (DD) vs 15.2 years (WD), p=0.02). Furthermore, all LPS cell lines and PDXs demonstrated high gene and protein expression of IGF2BP3. Conclusion: IGF2BP3 is highly expressed in a subset of LPS. Across independent datasets, IGF2BP3 is also a biomarker of disease progression and worse survival, and may stratify patients more effectively than histologic differentiation. Mechanistic studies of IGF2BP3 in LPS tumorigenesis and progression using aforementioned LPS cell lines and PDX models are ongoing. Citation Format: Kyle D. Klingbeil, Jack Pengfei Tang, Sarah M. Dry, Fritz C. Eilber, Dinesh S. Rao, Brian E. Kadera, Anusha Kalbasi. IGF2BP3 (IMP3) expression is associated with worse survival in well-differentiated/dedifferentiated (WD/DD) liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3490.