Recurrent MALAT1-GLI1 oncogenic fusion and GLI1 up-regulation define a subset of plexiform fibromyxoma.
Plexiform fibromyxomas are rare neoplasms, being officially recognized as a distinct entity among benign mesenchymal gastric tumours in the 2010 WHO Classification of Tumours of the Digestive System. Characteristically, these tumours 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 yet, the molecular and/or genetic features of these tumours are unknown. Here we describe a recurrent translocation, t(11;12)(q11;q13), involving the long non-coding gene metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and the gene glioma-associated oncogene homologue 1 (GLI1) in a subgroup of these tumours. The presence of the fusion transcript in our index case was confirmed using polymerase chain reaction (PCR) 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 (FFPE) 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 harbour GLI1/12q13 genomic alterations. In conclusion, overexpression of GLI1 through a recurrent MALAT1-GLI1 translocation or GLI1 up-regulation delineates a pathogenically distinct subgroup of plexiform fibromyxomas with activation of the Sonic Hedgehog signalling pathway. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Department of Human Genetics, KU Leuven and University Hospitals Leuven, Belgium.
Lien
L
Spans
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
Christopher Dm
CD
Fletcher
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Cristina R
CR
Antonescu
Department of Pathology, Cochin Hospital, Assistance Publique-, Hôpitaux de Paris, France.
Alexandre
A
Rouquette
Department of Pathology, Institut Bergonié, Bordeaux, France.
Jean-Michel
JM
Coindre
Department of Pathology, KU Leuven and University Hospitals Leuven, Belgium.
Raf
R
Sciot
Department of Human Genetics, KU Leuven and University Hospitals Leuven, Belgium.
Maria
M
Debiec-Rychter
D000293:Adolescent; D000328:Adult; D000368:Aged; D063646:Carcinogenesis; D005260:Female; D005350:Fibroma / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D050596:Oncogene Fusion / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D017423:Sequence Analysis, RNA; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D014178:Translocation, Genetic; D015854:Up-Regulation; D055815:Young Adult; D000071676:Zinc Finger Protein GLI1 / Q000235:genetics* / Q000378:metabolism
C400551:GLI1 protein, human; C557041:MALAT1 long non-coding RNA, human; D062085:RNA, Long Noncoding; D000071676:Zinc Finger Protein GLI1
GLI1; MALAT1; oncogenic fusion; plexiform fibromyxoma