Relationship Of Cul4a Gene Underexpression And Prognosis In Localized High-Risk Soft Tissue Sarcoma (Sts) Patients Of Limbs Or Trunk Wall.

10079 Background: Genes involved in cell cycle checkpoints and chromosome stability seem to be relevant in distant metastases appearance in STS. CUL4A is an E3 ubiquitin ligase that has been related to both p16 activation and maintenance of genomic stability. Expression of CUL4A has been scarcely described in some tumors with divergent outcome and there are no publications regarding its expression in STS patients. We previously showed that protein underexpression of CUL4A in metastatic STS was related to poor survival. Methods: The expression level of CUL4A was determined by quantitative qPCR and was retrospectively performed in a subset of 39 high-risk (grade 3, deep tumours and > than 5 cm) localized STS of limbs or trunk wall patients for which histological material and clinical data were available. Patients of this series were enrolled prospectively into a randomized clinical trial conducted by the Italian and Spanish sarcoma groups (ISG-GEIS 0101) comparing 3 vs 5 cycles of epirrubicin and ifosfamide. Differences in PFS, RFS, and OS were calculated using log-rank test Results: The median age was 51 years with a median follow-up of 52 months. The pathologic subtypes were undifferentiated pleomorphic sarcoma (35.3%), synovial sarcoma (23.5%) and mixed subtypes (41.2%). Location was distributed as inferior limbs (66.6%), upper limbs (25.5%) and trunk wall (7.9%). No relationship was seen between CUL4A expression and clinical variables (histologic types, location, size or response to neoadjuvant treatment). The expression level of CUL4A was significantly associated with events of progression, 65% vs 32%, p =0.037, for expression values under and over the median respectively. Regarding 4 y actuarial survival, there was a significant worse PFS and RFS for patients underexpressing CUL4A (p=0.041 and 0.009 respectively) and a trend towards worse OS (p=0.056). Conclusions: Expression of CUL4A gene shows a prognostic role in sarcomas within this high risk localized subset of STS patients. The outcome of this exploratory analysis is aligned with our hypothesis that genes implicated in cell cycle regulation and chromosome stability could play a relevant prognostic role in STS.