Novel FUS‐KLF17 and EWSR1‐KLF17 fusions in myoepithelial tumors

Abstract

Myoepithelial (ME) tumors of soft tissue and bone display a heterogeneous histologic spectrum and in about half of the cases harbor EWSR1 gene rearrangements. Despite rare case reports, the prevalence of FUS gene abnormalities and its related fusion partners remains undetermined among ME tumors. Therefore, we screened 66 EWSR1-negative ME tumors for FUS abnormalities by fluorescence in situ hybridization (FISH). In an index FUS-rearranged case, 3'-Rapid Amplification of cDNA Ends (RACE) was applied to identify the fusion partner. Results were further confirmed by RT-PCR, followed by FISH screening the entire cohort of FUS-rearranged and EWSR1-positive ME lesions lacking a known fusion partner. The correlation between genotype and clinicopathological features was also investigated. As a result, six (9%) FUS-rearranged cases were identified, spanning divergent age groups, tumor locations, and morphologic features. A novel FUS-KLF17 fusion was identified by 3’RACE in an 11 year-old girl with a foot lesion associated with locoregional metastases. Three additional cases with FUS-KLF17 fusions were identified and one KLF17 rearrangement (6.3%) was found among the 16 EWSR1-positive cases tested. The KLF17-related ME tumors affected younger patients and often exhibited trabecular growth in a myxohyaline stroma, but this genotype did not correlate with a malignant phenotype. In conclusion, a small subset of ME tumors harbor FUS rearrangements, two thirds of them being associated with KLF17 fusion. FUS FISH analysis is recommended in EWSR1-negative lesions in which a ME diagnosis is suspected. KLF17 is also a rare gene fusion partner to EWSR1-rearranged ME tumors.

EWSR1 Fusions With CREB Family Transcription Factors Define a Novel Myxoid Mesenchymal Tumor With Predilection for Intracranial Location

“…EWSR1 fusions have been identified in half of soft tissue myoepithelial tumors with various fusion partners, including POU5F1, PBX1, PBX3, ZNF444, and KLF17. 31,33,34 Only one myoepithelial tumor from a pelvic tumor of a 57 year-old man was reported with an EWSR1-ATF1 fusion, but the tumor had a typical myoepithelial immunophenotype. 35 …”

Round cell sarcoma with CIC‐DUX4 gene fusion: Discussion of the distinctive cytomorphologic, immunohistochemical, and molecular features in the differential diagnosis of round cell tumors

“…A subset (approximately 25%) of myoepithelial carcinomas exhibit nuclear loss of expression of SMARCB1/INI1, most likely secondary to functional loss of material on chromosome 22q11.2. Nearly one‐half of all myoepithelial carcinomas harbor rearrangements of EWSR1 (or rarely, alternate FUS ), and documented fusion partners thus far include POU5F1 (6p21), PBX1 (1q23), ZNF444 (19q23), ATF1 (12q13), PBX3 (9q33), and KLF17 (1p34) . Recently, homozygous deletions of the SMARCB1 gene have been reported in myoepithelial carcinomas lacking EWSR1 gene rearrangement …”

Clinicopathological features of five unusual cases of intraosseous myoepithelial carcinomas, mimicking conventional primary bone tumours, including EWSR1 rearrangement in one case

“…Demonstration of positive EWSR1 rearrangement in a musculoskeletal myoepithelial tumour displaying squamous differentiation is useful in differentiating this tumour from a dedifferentiated adamantinoma, as noted in the present study. Recently, EWSR1‐ negative myoepithelial tumours have been found to demonstrate FUS rearrangements in 10% of cases .…”