(P 393) DISTINCT SECONDARY MUTATIONAL LANDSCAPES ARE ASSOCIATED WITH NAB2–STAT6 FUSION BREAKPOINTS IN SOLITARY FIBROUS TUMORS

Objective: Solitary fibrous tumor (SFT) is a mesenchymal neoplasm driven by a NAB2::STAT6 fusion and exhibits variable clinical behavior. Emerging evidence suggests that specific fusion breakpoints carry prognostic significance: the NAB2 exon 6::STAT6 exon 16 (ex6::ex16) fusion is linked to younger age, aggressive behavior, and extrapulmonary location, while NAB2 exon 4::STAT6 exon 2 (ex4::ex2) is associated with older age, indolent course, and pulmonary origin. However, fusion-specific patterns of secondary genomic alterations remain largely unexplored.

Methods: We sought to assess the genomics of a cohort of SFTs, to identify if there are any distinct mutational signatures based on fusion breakpoints. FFPE tissue from 471 clinically advanced SFT patient tumors underwent comprehensive genomic profiling by a next-generation sequencing based in vitro diagnostic test (clinical trial assay based on FoundationOne®Heme) to evaluate all classes of genomic alterations (GAs) and tumor mutational burden (TMB, mutations/Mb). Overall, 54% were male and median age was 62 years.

Results: Seven distinct NAB2::STAT6 exon fusion configurations were identified in over 10 patients each (Table 1). The most prevalent was NAB2 exon 6::STAT6 exon 16 (ex6::ex16; n = 202), followed by ex4::ex2 (n = 56) and ex7::ex2 (n = 37). Patients with ex6::ex16 fusion were significantly younger (median age 55 years) compared to those with ex4::ex2 (66 years, p = 5.3×10⁻⁹) or ex7::ex2 (67 years, p = 7.6×10⁻⁸). Compared to the ex6::ex16 fusion, both ex4::ex2 and ex7::ex2 fusion variants were more commonly associated with lung primaries. Ex4::ex2 cases demonstrated a higher frequency of TP53 mutations (46% vs. 24%, p = 0.0014), whereas ex7::ex2 cases were enriched for CDKN2A/B mutation (19% vs. 2%, p = 0.0001).

Conclusion: SFTs demonstrate distinct molecular profiles based on NAB2::STAT6 fusion breakpoints. Specifically, ex4::ex2 cases are enriched for TP53 mutations, while ex7::ex2 cases show a higher frequency of CDKN2A/B alterations. The ex6::ex16 fusion is associated with younger patient age and extrapulmonary tumor location, consistent with prior reports. These findings suggest that fusion subtype and genomic profiling may inform diagnosis, prognosis, and potentially treatment frameworks.

Table 1. Clinicogenomic characteristics of solitary fibrous tumor (SFT) stratified by NAB2::STAT6 fusion exon breakpoints.