Clinicopathologic and molecular genetic characterization of low-grade fibromyxoid sarcoma, and cloning of a novel FUS/CREB3L1 fusion gene

Abstract

Low-grade fibromyxoid sarcoma (LGFMS) is an indolent, late-metastasizing malignant soft-tissue tumor that is often mistaken for either more benign or more malignant tumor types. Cytogenetic analyses have identified a recurrent balanced translocation t(7;16) (q32-34;p11), later shown by molecular genetic approaches to result in a FUS/CREB3L2 fusion gene. Whereas preliminary studies suggest that this gene rearrangement is specific for LGFMS, its incidence in this tumor type and the possible existence of variant fusion genes have not yet been addressed. For this purpose, a series of potential LGFMS were obtained from nine different soft-tissue tumor centres and subjected to molecular analysis as well as careful histopathologic review. Reverse transcriptasepolymerase chain reaction analysis disclosed a FUS/CREB3L2 fusion transcript in 22 of the 23 (96%) cases that remained classified as LGFMS after the histologic re-evaluation and from which RNA of sufficient quality could be extracted, whereas none of the cases that were classified as other tumor types was fusion-positive. In one of the tumors with typical LGFMS appearance, we found that FUS was fused to the CREB3L1 gene instead of CREB3L2. The proteins encoded by these genes both belong to the same basic leucine-zipper family of transcription factors, and display extensive sequence homology in their DNA-binding domains. Thus, it is expected that the novel FUS/CREB3L1 chimera will have a similar impact at the cellular level as the much more common FUS/CREB3L2 fusion protein. Taken together, the results indicate that virtually all LGFMS are characterized by a chimeric FUS/CREB3L2 gene, and that rare cases may display a variant FUS/CREB3L1 fusion.

FUS rearrangements are rare in ‘pure' sclerosing epithelioid fibrosarcoma

“…FUS rearrangements can be detected in up to 90% [19][20][21] of low-grade fibromyxoid sarcoma by fluorescence in-situ hybridization, whereas FUS/ CREB3L1/2 fusion transcripts have been reported to be detected in up to 96% of low-grade fibromyxoid sarcoma by RT-PCR. 9,[21][22][23] Therefore, there may be other genetic aberration/s that could conceivably link a subset of sclerosing epithelioid fibrosarcoma to low-grade fibromyxoid sarcoma. However, the prevalence of t(7;16) is substantially lower in sclerosing epithelioid fibrosarcoma than in lowgrade fibromyxoid sarcoma in this present study.…”

FUS-CREB3L2/L1–Positive Sarcomas Show a Specific Gene Expression Profile with Upregulation of CD24 and FOXL1

“…The clinical, cytogenetic, and fusion transcript data on 20 of the cases have been published before (5)(6)(7)(8). One tumor (case 14) had the FUS-CREB3L1 fusion transcript.…”

“…Gene expression array (cases [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19], IHC analyses (cases 1, 2, 10, 11, and 20-24), ICC (cases 5 and 6), and/or SNP array (cases 1-9) were carried out on 24 LGFMS cases listed in Table 1. The clinical, cytogenetic, and fusion transcript data on 20 of the cases have been published before (5)(6)(7)(8).…”

“…The discovery that LGFMS has a specific translocation t (7;16)(q33;p11), or in rare cases t(11;16)(p11;p11), has greatly facilitated the diagnosis (5,6). Through these translocations, the chimeric genes FUS-CREB3L2 or FUS-CREB3L1, respectively, are created.…”

“…Through these translocations, the chimeric genes FUS-CREB3L2 or FUS-CREB3L1, respectively, are created. At the molecular level, the 5 0 -part of FUS, encoding a transactivation domain, is fused to the 3 0 -part of CREB3L2 or CREB3L1, encoding a basic leucine zipper (bZIP) DNA-binding domain (5,7). A subset of LGFMS cases expresses the FUS-CREB3L2 fusion transcript but lacks the typical t(7;16) and instead harbors a supernumerary ring chromosome, which may contain the fusion gene, as the sole aberration (6,8).…”