The novel ASPL-TFE3 fusion arises from a t(X;17)(q25.3;p11.2) in two distinct human cancers, alveolar soft part sarcoma (ASPS), a lethal sarcoma of uncertain lineage, and a unique subset of pediatric renal adenocarcinomas. In these two tumor types, the gene fusions occur respectively through an unbalanced or balanced t(X;17). ASPL is a novel ubiquitously expressed gene that encodes a protein with no recognizable complex motifs, but is similar to unknown predicted proteins in several model organisms. The ASPL-TFE3 fusion replaces the N-terminal portion of TFE3 by the fused ASPL sequences, while retaining the DNA-binding domain of the TFE3 transcription factor, implicating transcriptional deregulation in the pathogenesis of this tumor. Preliminary transactivation and subcellular localization data support the function of ASPL-TFE3 as a transcription factor. ASPL-TFE3 is of special interest as the only chimeric transcription factor associated with malignancies of both mesenchymal and epithelial derivation. The overall goal of this proposal is to extend the understanding of the biology of these genes and tumors through functional studies, gene expression profiling, and molecular genetic analyses.
In Aim 1, the investigators will map the putative ASPL activation domain and perform a transactivation analysis of the reciprocal TFE3-ASPL product; examine transactivation of reporters driven by portions of endogenous TFE3 target promoters where cooperative interactions with other transcription factors are critical; and analyze specific ASPL-TFE3 protein-protein interactions.
In Aim 2, they will use microarray hybridizations to examine genes induced by TFE3 and ASPL-TFE3 in heterologous human mesenchymal and renal cell lines stably transfected with tetracycline-regulated TFE3 and ASPL-TFE3 constructs, and to establish and compare expression profiles of ASPS and pediatric renal adenocarcinomas containing ASPL-TFE3, and other major types of renal adenocarcinomas. Finally, in Aim 3, to address the hypothesis that the unbalanced structure of the t(X;17) in ASPS is driven by a growth advantage conferred to ASPS cells by the functional loss of a gene on 17q25.3 telomeric to ASFL, the investigators will examine polymorphic loci in Xp11.2->qter in ASPS from women to establish whether the t(X;17) of ASPS forms only in G2 or shows no intrinsic cell cycle preference; close sequence gaps in the ASFL-containing BAC and orient and order the sequence fragments, to determine which genes are telomeric to ASPL; analyze exceptional ASPS cases with a reciprocal t(X;17) for smaller deletions of 17q25.3->qter; and finally analyze selected candidate genes in the same region for inactivating mutations.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095785-02
Application #
6623425
Study Section
Special Emphasis Panel (ZRG1-PTHC (01))
Program Officer
Mietz, Judy
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
2
Fiscal Year
2003
Total Cost
$282,130
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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Argani, Pedram; Lae, Marick; Hutchinson, Brian et al. (2005) Renal carcinomas with the t(6;11)(p21;q12): clinicopathologic features and demonstration of the specific alpha-TFEB gene fusion by immunohistochemistry, RT-PCR, and DNA PCR. Am J Surg Pathol 29:230-40
Huang, Hsuan-Ying; Lui, Man Yee; Ladanyi, Marc (2005) Nonrandom cell-cycle timing of a somatic chromosomal translocation: The t(X;17) of alveolar soft-part sarcoma occurs in G2. Genes Chromosomes Cancer 44:170-6
Argani, Pedram; Ladanyi, Marc (2005) Translocation carcinomas of the kidney. Clin Lab Med 25:363-78
Argani, Pedram; Ladanyi, Marc (2003) Recent advances in pediatric renal neoplasia. Adv Anat Pathol 10:243-60
Argani, Pedram; Lui, Man Yee; Couturier, Jerome et al. (2003) A novel CLTC-TFE3 gene fusion in pediatric renal adenocarcinoma with t(X;17)(p11.2;q23). Oncogene 22:5374-8
Argani, Pedram; Lal, Priti; Hutchinson, Brian et al. (2003) Aberrant nuclear immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions: a sensitive and specific immunohistochemical assay. Am J Surg Pathol 27:750-61

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