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Department of Medical Genetics and Institute of Interdisciplinary Research, Faculty of Medicine, Free University of Brussels, 1070 Brussels, Belgium [P. H., H. E. H., G. O., G. V.]; Department of Human Genetics 417, University Hospital Nijmegen, 6500 HB Nijmegen, the Netherlands [M. A. J. W.]; and Departments of Human Genetics and Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan 48109-0638 [E. M. P.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In childhood, sporadic RCCs are mainly (but not exclusively) of tubulopapillary type (6)
and none of the genetic aberrations cited above have been thus far observed. Instead, anomalies in Xp11.2 region, such as the translocation t(X;1)(p11.2;q21) or its variants are recurrently reported (7)
. This t(X;1)translocation accounts for 
50% of the described cases (8)
and results in the fusion of a novel gene on chromosome 1, called PRCC, to TFE3 gene located on the X chromosome (9
, 10)
. TFE3 encodes a member of the basic helix-loop-helix family of transcription factors, which was originally demonstrated to bind to the µE3 element of the immunoglobulin heavy chain enhancer (11)
. PRCC is involved in the pre-mRNA splicing process (12)
.
Among the variants, translocations t(X;1)(p11.2;p34) and t(X;17)(p11.2;q25) have been the most frequently reported (8) , with the former resulting in the fusion of the TFE3 gene to the splicing factor gene PSF at chromosome 1p34 (13) . In the present study, we have identified the gene involved in the chromosome 17q25 translocation and characterized the fusion transcript. This gene on 17q25 has been coined RCC17. RCC17 contains a conserved UBX domain that is possibly involved in the ubiquitylation pathway but no relevant functional protein motif suggestive of its function.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Case 2 was a five-year-old-female of African origin admitted to the hospital because of fever and pain in the right hypochondria. Ultrasound scan revealed a retroperitoneal mass associated with mild hydronephrosis as well as a small nodule 10 mm in diameter in the upper pole of the left kidney. Histological examination of the kidney nodule showed a grade II papillary RCC (Fig. 1)
, and the retroperitoneal mass corresponded to an infiltration of regional kidney lymph nodes by this papillary RCC. Further analysis confirmed that this tumor did not extend beyond the regional lymph nodes. This tumor was classified as pT1aN1M0 according to the TNM staging system.
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FISH.
To delineate the breakpoint on chromosome 17q25, several P1 and BAC clones spanning the 17q25.2–25.3 chromosomal regions at (proximal to distal) D17S937, D17S939, D17S802, TK1, D17S836, ERBA2L, and ILF1 were used (16)
. A 3.2-kb TFE3 clone (9)
, a 1.8-kb RCC17 clone (corresponding to the cDNA identified in the present study), and 
satellite probes for chromosomes X and 17 (DXZ1 and D17Z1; Oncor, Gaithersburg, MD) were also used. All of the FISH analyses were performed as described previously (14)
on metaphases from the long-term cell line containing the t(X;17) (case 1) and on metaphases from a short-term cell culture (case 2). Chromosomal preparations from normal peripheral leukocytes were used with the RCC17 cDNA probe.
5' RACE PCR.
5' RACE PCR was performed on poly(A)+RNA extracted from case 1 using the 5' RACE system for rapid amplification of cDNA ends kit (Life Technologies, Inc., Paisley, PA4 9RF, United Kingdom). Poly(A)+ RNA was isolated from the long-term cell line t(X;17) metaphases and using the Micro-FastTrack kit (Invitrogen, Carlsbad, CA). In brief, 500 ng of poly(A)+RNA were reverse transcribed with a TFE3-specific primer 5'-CAGTTCCTTGATCCTGTCG-3'. The first and second round PCRs were performed according to the manufacturer’s instructions with the specific TFE3 reverse primers 5'-CGCCTGCGACGCTCAATTAG-3' and 5'-CGTTTGATGTTGGGCAGCTC-3', respectively.
RT-PCR.
Total RNA was isolated from the long-term cell line containing the t(X;17) (case 1) and from a tumor sample (case 2) with the Trizol Reagent kit (Life Technologies, Inc.) and subsequently treated with DNase using a DNA-free kit (Ambion, Austin, TX). Reverse transcription was performed with the MMLV reverse transcriptase and random hexamers (Life Technologies, Inc.) according to the manufacturer’s protocol. The RCC17-TFE3 hybrid transcripts were detected by amplification with the RCC17 primer 5'-GTTGCCGAAGTCCCTCTCCA-3' (forward primer) and the TFE3 primer 5'-CGCCTGCGACGCTCAATTAG-3' (reverse primer). The reciprocal TFE3-RCC17 hybrid transcripts were detected using the TFE3 primer 5'-CGCAAGTGCCCAGCCACT-3' (forward primer) and the RCC17 primer 5'-GCCCCCTCCTCAGCAGCT-3' (reverse primer). The presence of normal RCC17 transcripts was assessed with primers 5'-GCCATTTTCCACAGATCAGG-3' (forward primer) and 5'- GCTGGAGAGGGACTTCGG-3' (reverse primer). Normal TFE3 transcripts were detected using the same forward and reverse TFE3 primers described above. For both RCC17-TFE3 and TFE3-RCC17 fusion transcripts, amplification conditions were 94°C for 60 s, 60°C for 30 s, and 72°C for 60 s (30 cycles) using the standard Taq DNA polymerase (Applied Biosystems, Foster City, CA) in a final volume of 50 µl. For normal TFE3 transcripts, the PCR conditions were similar except for the fact that 35 cycles were performed. PCR amplifications for the normal RCC17 transcript were done with the PCR Qiagen kit (Qiagen, Valencia, CA) according to the manufacturer’s protocol. Amplification conditions were 94°C for 60 s, 55°C for 30 s, and 72°C for 60 s (35 cycles) in a final volume of 50 µl. The products were separated by electrophoresis in a 2% agarose gel followed by staining with ethidium bromide.
Northern Blot Analysis.
An-839 bp fragment, representing the 5' part of the cDNA identified in this study, was used as a probe to screen various adult human tissue poly(A)+RNAs including heart, brain, liver, skeletal muscle, kidney, pancreas, and placenta.
DNA Sequencing.
For sequence analysis, PCR products were either subcloned with the TA Cloning kit (Invitrogen) following instructions of the manufacturer or were sequenced directly after having been isolated by electrophoresis in 1% agarose gels and purified with the Geneclean II kit (BIO101, Vista, CA) when necessary. The 5' Race PCR product from case 1, the RCC17-TFE3 RT-PCR product from case 2, and both strands of the RCC17 gene cDNA were sequenced with the dideoxymethod using the BigDye Terminator Cycle Sequencing Kit (Applied Biosystems). The different primers used for sequencing were the M13 forward and reverse primers (for subcloned PCR products), the TFE3 reverse primer 5'-CGCCTGCGACGCTCAATTAG-3', and several RCC17 primers given in Table 1
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RESULTS |
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Identification of the RCC17 Gene.
Sequence of the 5' Race product from case 1 diverged from the normal TFE3 sequence at position corresponding to the TFE3 exon3-exon4 junction. Searches of the EMBL databases showed that the unknown 5'sequence had 339 bp of overlap with a 183-kb homo sapiens chromosome clone RP11-498C9 consisting of 16 unordered contigs (GenBank accession no. ACO69004), from which 71 bp of additional sequence at the 5' end of the unknown sequence were also identified (Fig. 2)
. These additional nucleotides completed the 5' end of the coding sequence because they contained an ATG codon in agreement with the Kozak consensus sequence (17)
and displayed an in-frame TGA stop codon located 36 bp upstream of the initiation triplet. The 3' end of the novel sequence had 113 bp of overlap with a 227-bp EST of human colon (Stratagene, GenBank accession no. AA056378) which, in turn, matched with a 409-bp human placental EST (GenBank accession no. R62723). This last one yielded 382 bp of additional sequence on the 3'end of our unknown sequence and showed 255 bp of overlap with a 387 bp Soares breast homo sapiens cDNA clone (GenBank accession no. H51880). A total of 17 additional overlapping ESTs were identified corresponding to the 3' end of the cDNA (GenBank accession no. AW302150, AW302160, W63713, AA303110, AW194381, AI923728, AA485942, AA972192, AI024586, AI825028, AI985056, AI031531, AI625114, AI826958, AA766699, AA782421, and AW452860). Altogether, they gave an additional sequence of 642 bp and completed the 3' end of the unknown cDNA including the poly(A) tail. To test the colinearity of the unknown 5' Race product and the 17 additional ESTs, we performed two independent PCRs on human fetal brain cDNA (Clontech, Palo Alto, CA) and human placental cDNA, using a forward and a reverse primer located at position 804–823 (corresponding to the 3' end of the unknown cDNA) and position 1545–1562 of the composite sequence, respectively. For both tissues, we successfully amplified a fragment of 760 bp that was cloned and sequenced. The nucleic acid sequences obtained were similar to the 3' part of the composite sequence. The 71 additional bp yielded by the human chromosomal clone RP11-498C9, the unknown clone from the 5' Race PCR product and the different overlapping ESTs, were then assembled into one single contig resulting in an open reading frame of 1662 nucleotides (Fig. 2)
. Several PCRs were performed from human placental cDNA with primers scattered along the whole length of this sequence and giving overlap amplicons of 300–400 bp. Direct sequencing of each amplicon was performed, yielding a contig with continuous open reading frame. The corresponding gene encoding a 553-amino acid putative protein was named RCC17 (for RCC chromosome 17; Fig. 3
).
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. Sequence comparisons of the predicted RCC17 protein using the BLAST software and the PROSITE database did not show significant similarity to any known proteins, including other fusion partners of TFE3, namely PRCC, PSF, and NonO. However, searches with the SMART web-site tool (18)
revealed within the 3' portion of RCC17 (residues 382–464) a significant similarity with a UBX domain (Fig. 3)
, a poorly characterized motif present in some ubiquitin-regulatory proteins. Moreover, three P-X-X-P motifs, which are known to bind proteins with SH3 domains (19)
, were observed at residues 241–244, 258–261, and 276–279 (Fig. 3)
.
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). The first and second exons were localized within the contig nr 8 (assembly name) of RP11-498C9 and separated by an intronic sequence of 1434 bp. Starting from the initiation codon, exon 1 extended down to nucleotide 102, whereas exon 2 had a length of 56 bp. The third and fourth exons were localized within the contig nr 12 (assembly name) of RP11-498C9 and were separated by an intron of 1836 bp. Exons 3 and 4 were 115 and 101 bp long, respectively.
Expression of RCC17-TFE3 Transcripts.
The presence of a RCC17-TFE3 hybrid transcript was demonstrated by RT-PCR using a 5' RCC17 primer and a 3' TFE3 primer. A product of the predicted size (321 bp) was obtained in both PRCC cases but not in several cancer cell lines including K562 (chronic myelogenous leukemia cell line), HL60 (acute myeloid leukemia cell line), and MZ2mel (melanoma cell line; Fig. 5
). Sequencing of the RT-PCR product of case 2 demonstrated an identical RCC17-TFE3 junction as for the 5' Race PCR product obtained in case 1. Thus, in both cases, the 311-amino acids NH2-terminal region of RCC17 was fused to the COOH-terminal DNA binding domain (bHLH and LZ regions) of TFE3. Reciprocal TFE3-RCC17 hybrid transcripts were also detected in both cases (data not shown).
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. The distribution of RCC17 gene expression was explored by Northern blotting and RT-PCR. Hybridization of a RCC17 probe to a Northern blot with a collection of poly(A)+RNA from various tissues detected a 2-kb transcript weakly expressed in heart, placenta, liver, skeletal muscle, kidney, and pancreas but not in brain (Fig. 6)
. The RCC17 expression study was completed by RT-PCR on various human adult tissue cDNA (Clontech) including whole brain with the same RCC17 primers as mentioned above. An amplicon of the expected size (468 bp) was observed in all of the samples, demonstrating ubiquitous expression of the RCC17 gene (Fig. 7)
. Moreover, a Northern blot analysis performed on fetal brain demonstrated a 2-kb transcript also (data not shown).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The TFE3 gene belongs to the bHLH-Zip family of transcription factors and has been initially identified as a protein binding to the µE3 element of the immunoglobulin heavy-chain enhancer (11) . However, its ubiquitous expression indicates that this gene must play a much broader role in transcriptional control. For example, it has recently been suggested that the TFE3 gene may act on phosphate transport in the kidney by regulating transcription of the type II sodium-dependent phosphate (Na/Pi) cotransporters (NPT2; Ref. 20 ). These are major transporters associated with renal Pi reabsorption and are located at the apical membrane of renal proximal tubular cells. TFE3 would also have a function in the regulation of melanogenesis through the control of tyrosinase and Tyrp1 gene expression (21) . Moreover, TFE3, in cooperation with the SMAD3 protein, and through the TGF-ß-activated signal transduction pathway, activates the plasminogen activator inhibitor-1 gene (PAI1; Ref. 22 ); a factor involved in cancer cell invasion and angiogenesis (23) .
The presence of some P-X-X-P motifs in RCC17 suggests that the encoded protein could bind proteins with SH3 modules; domains that are known to mediate protein-protein interactions. (19) . Because these P-X-X-P motifs are included in the 5' RCC17 fragment that fuses to TFE3, the RCC17/TFE3 chimeric transcript would enact novel regulatory interactions of TFE3 with SH3-containing proteins. RCC17 contains also an UBX domain located within its COOH-terminal portion. The UBX domain is observed in some human proteins such as hFAF1 (24) , REP8 (25) , and the predicted p47 protein (GenBank accession no. NM 018839.1). The functional properties of this motif remains unclear, but its cooccurrence with the ubiquitin-regulatory UBA domain (26) in some proteins [human predicted protein LOC51035 (GenBank accession no. XM 012093.1) and HUMORF (GenBank accession no. M68864)] suggests that it is involved in the ubiquitylation pathway.
Finally, RCC17 does not possess any peculiar domains suggestive of its function. Nevertheless, its role could tentatively be predicted from the functional data available from the other TFE3 fusion genes. Indeed, PRCC, PSF, and NonO are all involved in the pre-mRNA splicing process (12 , 13) , and, alteration of their function as a possible consequence of fusion to TFE3 could result in inappropriate splicing of specific transcripts and in tumorigenesis (12) . Although RCC17 does not show any homology with other TFE3 fusion partners, it may be hypothesized that RCC17 could also represent a splicing factor.
Because both the RCC17/TFE3 and TFE3/RCC17 fusion transcripts were expressed in the tumoral tissue, their respective role in carcinogenesis remains to elucidate. However, it has been demonstrated by means of Zebra-luciferase reporter assays that the PRCC/TFE3 fusion protein in t(X;1)(p11;q21)papillary RCC, has a transactivating capability that is 3-fold higher than for the wild-type TFE3, whereas the activation of the reciprocal product TFE3/PRCC is not significantly elevated, compared with that caused by the normal PRCC protein (27) . This suggests that generation of the PRCC/TFE3 fusion protein (and not of the reciprocal product) is the most critical factor for tumor development.
An interesting point would be to determine whether the various partner genes fused with TFE3 have a different functional importance and to determine their possible influence on tumor morphology and clinical outcome. In human cancer exhibiting variant translocations (i.e., one common gene fused to different possible partner genes), there are several examples demonstrating a significant relation between the type of fusion and the morphological findings as well as the prognosis. In synovial sarcoma a para-articular soft tissue tumor of unknown histogenesis, the morphological aspects vary according to the SYT-SSX1 or SYT-SSX2 fusion transcript (28) . Moreover, the metastasis-free survival is significantly longer among patients with the SYT-SSX2 fusion transcript. Clinical differences attributable to genetic heterogeneity are also observed in alveolar rhabdomyosarcoma, an aggressive pediatric soft-tissue tumor with striated muscle differentiation. Indeed, tumors with the PAX7-FKHR fusion more often present as a localized disease and are associated with longer event-free survival as compared with the PAX3-FKHR tumors (29) .
Of note, the TFE3 gene displays some variability of genomic breakpoints among the different types of Xp11 fusion transcripts. In our two cases, the breakpoint was similar to that observed in NonO-TFE3 and PSF-TFE3 hybrid transcripts [corresponding to the t(X;1)(p11.2;p34) and inv(X)(p11.2;q12) bearing RCC, respectively], and localized between exons 3 and 4 of the TFE3 gene. The fusion protein generated lacks the TFE3 acidic activation domain, unlike the PRCC-TFE3 fusion type [corresponding to the translocation t(X;1)(p11;q21)], which retains the TFE3 acidic activation domain, because the breakpoint is localized at the exon 1–2 junction. It may be that this structural heterogeneity has no functional significance. However, it has been demonstrated in Ewing sarcoma, a primitive neuroectodermal tumor of children and young adults, that structural variations in the EWS-FLI1 fusion gene correlated closely with the various clinical behaviors exhibited by this neoplasm (30) .
Molecular studies on large series of childhood RCC are needed to determine whether fusion of the TFE3 gene to different partners as well as various TFE3 breakpoints correlate with particular morphological and clinical phenotypes.
Surprisingly, after initial submission of the present article, it has been reported that the same t(X;17)fusion transcript was present in the ASPS (31)
, a soft tissue tumor of unclear histogenesis that shows histological features and clinical behaviors different from the RCCs. The TFE3 breakpoint in ASPS was in the majority of cases similar to the one observed in t(X;17) RCCs, i.e., located between TFE3 exons 3 and 4. In few cases, this breakpoint occurred within intron 2. The novel gene on chromosome 17q25 was designated ASPL (for ASPS locus) and showed the same breakpoint as the RCC17 gene. ASPL matched perfectly the RCC17 sequence except for the absence in RCC17 of a 90-nucleotide segment corresponding to the 3' portion of ASPL exon 2. When we had compared the 5' end of RCC17 with the human chromosome clone RP11-498C9 (see "Results" and Fig. 2
), this 90-nucleotide fragment was considered as part of the RCC17 intron 2 in accordance with appropriate exon/intron junctions. This difference, which may correspond to alternative splicing, led Ladanyi et al.
(31)
to assign the initiating codon of ASPL 321 nucleotides downstream as compared with the initiating ATG of RCC17. The existence of the RCC17 sequence as determined here is confirmed by numerous additional ESTs [including, e.g., a pediatric acute myelogenous leukemia cell cDNA clone (GenBank accession no. BE 241763.1) and a Soares breast 3Nb HBst homo-sapiens cDNA clone (GenBank accession no. H45871.1)] showing perfect alignment with the 5' segment of RCC17.
The implication of identical cytogenetic and molecular anomalies in tumors of different sites is not unprecedented. In congenital mesoblastic nephroma (CMN) and congenital fibrosarcoma (CFS), the same ETV6-NTRK3 fusion transcript has been identified (32) . Both tumors share a very similar histological pattern, and the discovery of an identical fusion transcript gives strong evidence that they represent a single neoplastic entity occurring in different sites (32) . In PRCC, the t(X;17)(p11;q25) translocation is reciprocal, whereas it seems to be unbalanced in ASPS (14 , 33) . It is conceivable that in ASPS, the occurrence of a chimerical fusion gene would be associated with a still-undefined loss and/or gain of function, thus accounting for the different phenotypes of ASPS and PRCC.
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FOOTNOTES |
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1 P. H. is a recipient of the "Fondation Erasme." 
2 To whom requests for reprints should be addressed, at the Department of Medical Genetics and Institute of Interdisciplinary Research, Faculty of Medicine, Campus Erasme, 808 route de Lennik, 1070 Brussels, Belgium. Phone: 32-2-555-41-45; Fax: 32-2-555-42-12; E-mail: pheimann{at}ulb.ac.be
3 The abbreviations used are: RCC, renal cell carcinoma; FISH, fluorescence in situ hybridization; 5' RACE PCR, 5' rapid amplification of cDNA ends PCR; RT-PCR, reverse transcription-PCR; ASPS, alveolar soft part sarcoma; UBA and UBX, ubiquitin regulatory domain protein; TGF-ß, transforming growth factor ß; EST, expressed sequence tags; ISCN, international system for human cytogenetic nomenclature; MMLV, moloney murine leukemia virus; GAPDH, glyceraldehyde phosphate deshydrogenase.
Received 12/13/00. Accepted 3/20/01.
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