[61] Recurrent NOTCH2 and NOTCH3 Gene Rearrangements in Benign and Malignant Glomus Tumors

Juan Miguel Mosquera, Andrea Sboner, Lei Zhang, Naoki Kitabayashi, Chung-Liang Chen, Yung Shao Sung, Basma Basha, Mark A Rubin, Cristina R Antonescu. Weill Medical College of Cornell University, New York, NY; Memorial Sloan-Kettering Cancer Center, New York, NY; Weill Cornell Medical College in Qatar, Doha, Qatar

Background: Glomus tumors (GT) are members of a heterogeneous family of tumors of peri-vascular modified smooth muscle cells, including among others myopericytoma, myofibroma/tosis, and angioleiomyoma. However, there are no molecular studies to date to investigate if this morphologic spectrum also shares similar genetic abnormalities.
Design: Next generation RNA sequencing was performed on one malignant visceral GT (glomangiosarcoma). Data was analyzed using FusionSeq, a modular computational tool developed to discover gene fusions. Gene fusion candidates were validated by FISH, RT-PCR and Sanger sequencing. Additional cases interrogated were 24 benign GT/glomangiomas (20 soft tissue; 4 visceral), 1 multifocal/hereditary GT, 2 visceral glomangiosarcomas, 5 myopericytomas, 7 myofibroma/toses, and 12 angioleiomyomas.
Results: A gene fusion involving NOTCH2 and a genomic location in chromosome 5 was identified in the sequenced index case, and then validated by FISH and RT-PCR. As both NOTCH2 and NOTCH3 genes have similar functions in regulating vascular smooth muscle development and homeostasis, we investigated our cases for structural and numerical abnormalities in both genes by FISH. NOTCH2 gene rearrangements were identified in 3/3 visceral glomangiosarcoma and 1/4 visceral benign GT. Rearrangements in either NOTCH2 or NOTCH3 were identified in 14/20 (60%) soft tissue GT, including 1/6 digital GT from one NF1 patient. Only 1/12 (8.3%) angioleiomyomas showed NOTCH2 gene rearrangement, while all the myopericytomas and myofibroma/tosis cases were negative.
Conclusions: We describe for the first time recurrent NOTCH2 and NOTCH3 rearrangements in benign and malignant, visceral and soft tissue glomus tumors and in rare cases of angioleiomyoma. These findings suggest a common pathogenesis for at least some members of the perivascular myoid family of tumors. Potential use of Notch inhibitors in treatment of aggressive/malignant forms of GT has yet to be determined.
Category: Bone & Soft Tissue

Tuesday, March 5, 2013 8:00 AM

Proffered Papers: Section G, Tuesday Morning

 

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