RecurrentMALAT1-GLI1oncogenic fusion andGLI1up-regulation define a subset of plexiform fibromyxoma

Abstract

Plexiform fibromyxomas are rare neoplasms, being officially recognized as a distinct entity among benign mesenchymal gastric tumors in the 2010 WHO Classification of Tumors of the Digestive System. Characteristically, these tumors have a multinodular/plexiform growth pattern, and histologically contain variably cellular areas of bland myofibroblastic type spindle cells embedded in an abundant myxoid matrix, rich in capillary-type vessels. As of yet, the molecular and/or genetic features of these tumors are unknown. Here, we describe a recurrent translocation t(11;12)(q11;q13) involving the MALAT1 (metastasis associated lung adenocarcinoma transcript 1) long noncoding gene and the GLI1 (glioma-associated oncogene homologue 1) gene in a subgroup of these tumors. The presence of the fusion transcript in our index case was confirmed using polymerase chain reaction on genomic DNA followed by Sanger sequencing. We showed that the truncated GLI1 protein is overexpressed and retains its capacity to transcriptionally activate its target genes. A specific FISH assay was developed to detect the novel MALAT1-GLI1 translocation in formalin-fixed paraffin-embedded material. This resulted in the identification of two additional cases with this fusion, and two cases with polysomy of the GLI1 gene. Finally, immunohistochemistry revealed that the GLI1 protein is exclusively overexpressed in those cases that harbor GLI1/12q13 genomic alterations. In conclusion, overexpression of GLI1 through a recurrent MALAT1-GLI1 translocation or GLI1 upregulation delineates a pathogenically distinct subgroup of plexiform fibromyxomas with activated Sonic Hedgehog signaling pathway.

Gastric Plexiform Fibromyxoma: A Great Mimic of Gastrointestinal Stromal Tumor (GIST) and Diagnostic Pitfalls

“…3 A recent study also mentioned that the gene glioma-associated oncogene homologue 1 (GLI1) may be present in a subgroup of these tumors. 10 In our series, we had an unusual consultation case that has nuclear pleomorphism, increased mitotic activity with three mitotic figures in 10 highpower field with six PHH3 positive cells in 5 mm 2 area, and 30% of Ki-67 proliferation index as well as a synchronous 0.7 cm GIST. This tumor did not show lymphovascular invasion or perineural invasion.…”

An Unbalanced Chromosome Translocation Between 7p22 and 12q13 Leads to ACTB-GLI1 Fusion in Pericytoma

“…Breakpoint positions are indicated by arrows. Recently, the MALAT1-GLI1 fusion gene was reported in a subset of plexiform fibromyxomas, in gastroblastomas, and in epithelioid tumors with metastatic potential (5,34,35). The MALAT1 gene (on 11q13.1) is ubiquitously expressed and produces a long non-coding RNA (36,37).…”

“…The MALAT1 gene (on 11q13.1) is ubiquitously expressed and produces a long non-coding RNA (36,37). Part of MALAT1 was fused to exon 6 (plexiform fibromyxomas) or to the last 19 nt of the 145 bp long exon 5 (gastroblastoma) of GLI1 (34,35). Spans et al (34) showed that the truncated GLI1 protein (lacking exons 1-5) was transcriptionally active.…”

Chronic Expanding Hematoma with a t(11;19)(q13;q13) Chromosomal Translocation

“…Studies have shown that MALAT1 is dysregulated and plays a critical role in the development and progression of various cancer types (34)(35)(36)(37). A recurrent MALAT1-GLI1 fusion, resulting in GLI family zinc finger 1 (GLI1) overexpression, was described in gastroblastomas and plexiform fibromyxomas (38,39).…”