In-frame internal tandem duplications of BCOR occur in 100% of clear cell sarcomas of the kidney (CCSK).

  • Major finding: In-frame internal tandem duplications of BCOR occur in 100% of clear cell sarcomas of the kidney (CCSK).

  • Concept:BCOR alterations are highly specific to CCSK and are not found in other pediatric renal tumors.

  • Impact:BCOR duplications provide insight into the etiology of CCSK and may facilitate its diagnosis.

Clear cell sarcoma of the kidney (CCSK) is one of the most common pediatric renal cancers, but it is frequently misdiagnosed due to its histologic similarity to other renal tumors and its lack of distinguishing molecular or immunohistochemical markers. Based on their previous observation that CCSK has a distinct DNA methylation signature and the reported links between DNA methylation and histone modifications, Ueno-Yokohata and colleagues evaluated histone modifiers in CCSK and found that BCL6 corepressor (BCOR), a component of noncanonical Polycomb repressive complex 1 (PRC1), was hypomethylated and highly expressed in CCSK. However, the PCR products were larger than expected for wild-type BCOR, and sequencing revealed partial tandem duplications of the 3′ coding sequence of BCOR in every tumor. Screening of 193 non-CCSK primary pediatric renal tumors did not identify any BCOR alterations, suggesting that BCOR internal tandem duplications are specific to CCSK. All of the BCOR internal tandem duplications were in frame and resulted in the addition of 30 to 38 amino acids within a domain necessary for binding to the noncanonical PRC1 subunit PCGF1, raising the possibility that these duplications may affect the function of BCOR as an epigenetic modifier. The findings that the aberrant alleles were expressed in CCSK samples and that expression of mutant BCOR promoted anchorage-independent growth in vitro suggest that BCOR internal tandem duplications lead to a gain of function and are oncogenic, which contrasts with BCOR mutations identified in other cancer types that appear to cause loss of BCOR activity. The identification of in-frame internal tandem duplications of BCOR as a specific feature of CCSK thus provides insight into the underlying biology of CCSK, and may also help to distinguish CCSK from other pediatric renal tumors.

Ueno-Yokohata H, Okita H, Nakasato K, Akimoto S, Hata J, Koshinaga T, et al. Consistent in-frame internal tandem duplications of BCOR characterize clear cell sarcoma of the kidney. Nat Genet 2015 Jun 22 [Epub ahead of print].