The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25

Alveolar soft part sarcoma (ASPS) is an unusual tumor with highly character istic histopathology and ultrastructure, controversial histogenesis, and en igmatic clinical behavior. Recent cytogenetic studies have identified a rec urrent der(17) due to non-reciprocal t(X;17)(p11.2;q25) in this sarcoma, To define the interval containing the Xp11,2 break, we first performed FISH o n ASPS cases using YAC probes for OA TLI (Xp11,23) and OATL2 (Xp11,21), and cosmid probes from the intervening genomic region. This localized the brea kpoint to a 160 kb interval. The prime candidate within this previously ful ly sequenced region was TFE3, a transcription factor gene known to be fused to translocation partners on 1 and X in some papillary renal cell carcinom as. Southern blotting using a TFE3 genomic probe identified non-germline ba nds in several ASPS cases, consistent with rearrangement and possible fusio n of TFE3 with a gene on 17q25, Amplification of the 5' portion of cDNAs co ntaining the 3' portion of TFE3 in two different ASPS cases identified a no vel sequence, designated ASPL, fused in-frame to TFE3 exon 4 (type 1 fusion ) or exon 3 (type 2 fusion), Reverse transcriptase PCR using a forward prim er from ASPL and a TFE3 exon 4 reverse primer detected an ASPL-TFE3 fusion transcript in all ASPS cases (12/12: 9 type 1, 3 type 2), establishing the utility of this assay in the diagnosis of ASPS. Using appropriate primers, the reciprocal fusion transcript, TFE3-ASPL, was detected in only one of 12 cases, consistent with the non-reciprocal nature of the translocation in m ost cases, and supporting ASPL-TFE3 as its oncogenically significant fusion product. ASPL maps to chromosome 17, is ubiquitously expressed, and matche s numerous ESTs (Unigene cluster Hs.84128) but no named genes. The ASPL cDN A open reading frame encodes a predicted protein of 476 amino acids that co ntains within its carboxy-terminal portion of a UBX-like domain that shows significant similarity to predicted proteins of unknown function in several model organisms. The ASPL-TFE3 fusion replaces the N-terminal portion of T FE3 by the fused ASPL sequences, while retaining the TFE3 DNA-binding domai n, implicating transcriptional deregulation in the pathogenesis of this tum or, consistent with the biology of several other translocation-associated s arcomas.