Abstract
Somatic mutations in the ARID1A tumor-suppressor gene have been frequently identified in ovarian clear cell carcinoma (CCC) cases. BAF250a encoded by ARID1A is a member of the SWI/SNF complex, but the expression and mutation status of other SWI/SNF subunits have not been explored. The current study aimed to elucidate the biological and clinical significance of the SWI/SNF complex subunits, by assessing the expression and mutation status of SWI/SNF subunits, and distinct genomic aberrations associated with their expression. Of 82 CCC specimens, 38 samples presented no BAF250a expression, and 50 samples exhibited the loss of at least one subunit of the SWI/SNF complex. Cases which lack at least one SWI/SNF complex component exhibited significantly more advanced stages, faster growth and stronger nuclear atypia compared with SWI/SNF-positive samples (p<0.05). Although BAF250a expression is not related to poor prognosis, the group presenting the loss of at least one SWI/SNF complex subunit exhibited significantly shorter overall and progression-free survivals (p<0.05). A multivariate analysis suggested that the expression status of the SWI/SNF complex serves as an independent prognostic factor (p<0.005). The cases positive for all SWI/SNF subunits demonstrated significantly greater DNA copy number alterations, such as amplification at chromosomes 8q.24.3 and 20q.13.2-20q.13.33 (including ZNF217) and deletion at chromosomes 13q12.11-13q14.3 (including RB1), 17p13.2-17p13.1 (including TP53) and 19p13.2-19p13.12. In conclusion, the CCCs exhibiting the loss of one or multiple SWI/SNF complex subunits demonstrated aggressive behaviors and poor prognosis, whereas the CCCs with positive expression for all SWI/SNF components presented more copy number alterations and a favorable prognosis.
Highlights
Ovarian cancer is the most devastating gynecological malignancy in the world and is a heterogeneous disease with distinct clinicopathological and molecular features [1, 2]
BAF250a encoded by ARID1A is a member of the SWItch/Sucrose Non-Fermentable (SWI/ SNF) chromatin remodeling complex, which comprises polymorphic assemblies of at least 14 subunits encoded by 28 genes, generating an extensive diversity of complexes with specialized functions in specific tissues [7,8,9,10]
Representative immunohistochemistry results for nine SWI/SNF complex subunits (BAF250a, BAF250B encoded by ARID1B, BRM encoded by SMARCA2, BRG1 encoded by SMARCA4, BAF155 encoded by SMARCC1, BAF170 encoded by SMARCC2, SNF5 encoded by SMARCB1, BCL11A and BAF180 encoded by PBRM1) are shown in Supplementary Figure S1
Summary
Ovarian cancer is the most devastating gynecological malignancy in the world and is a heterogeneous disease with distinct clinicopathological and molecular features [1, 2]. Recent genome-wide studies in ovarian CCC have identified somatic mutations in www.impactjournals.com/oncotarget. Several subunits of the SWI/SNF complex have been reported to possess tumor-suppressive functions in the malignancies of several organs [7,8,9], the expression and mutation status of SWI/SNF complex subunits, with the exception of BAF250a, have yet to be explored in ovarian CCC. The biological and functional roles of the SWI/SNF complex in ovarian CCC have yet to be elucidated. The expression of SWI/SNF complex subunits and BAF250a was assessed to explore the biological and clinical significance of these proteins in ovarian CCC
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