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Novel MEIS1-NCOA2 Gene Fusions Define a Distinct Primitive Spindle Cell Sarcoma of the Kidney.

ABSTRACT: We describe 2 cases of a distinct sarcoma characterized by a novel MEIS1-NCOA2 gene fusion. This gene fusion was identified in the renal neoplasms of 2 adults (21-y-old male, 72-y-old female). Histologically, the resected renal neoplasms had a distinctively nodular appearance, and while one renal neoplasm was predominantly cystic, the other demonstrated solid architecture, invasion of perirenal fat, and renal sinus vasculature invasion. The neoplasms were characterized predominantly by monomorphic plump spindle cells arranged in vague fascicles with a whorling pattern; however, a more primitive small round cell component was also noted. Both neoplasms were mitotically active and one case showed necrosis. The neoplasms did not have a distinctive immunohistochemical profile, though both labeled for TLE1. The morphologic features are distinct from other sarcomas associated with NCOA2 gene fusions, including mesenchymal chondrosarcoma, congenital/infantile spindle cell rhabdomyosarcoma, and soft tissue angiofibroma. While we have minimal clinical follow-up, the aggressive histologic features of these neoplasms indicate malignant potential, thus warranting classification as a novel subtype of sarcoma.

SUBMITTER: Argani P

PROVIDER: S-EPMC6719684 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Novel MEIS1-NCOA2 Gene Fusions Define a Distinct Primitive Spindle Cell Sarcoma of the Kidney.

Argani Pedram P Reuter Victor E VE Kapur Payal P Brown James E JE Sung Yun-Shao YS Zhang Lei L Williamson Richard R Francis Glen G Sommerville Scott S Swanson David D Dickson Brendan C BC Antonescu Cristina R CR

The American journal of surgical pathology 20181101 11

We describe 2 cases of a distinct sarcoma characterized by a novel MEIS1-NCOA2 gene fusion. This gene fusion was identified in the renal neoplasms of 2 adults (21-y-old male, 72-y-old female). Histologically, the resected renal neoplasms had a distinctively nodular appearance, and while one renal neoplasm was predominantly cystic, the other demonstrated solid architecture, invasion of perirenal fat, and renal sinus vasculature invasion. The neoplasms were characterized predominantly by monomorph ...[more]

PMID: 30179902

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Project description:Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway. This has led to PLGG clinical trials utilizing RAF- and MAPK pathway-targeted therapeutics. Whole-genome profiling of PLGGs has also identified rare gene fusions involving another RAF isoform, CRAF/RAF1, in PLGGs and cancers occuring in adults. Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways. Although ATP-competitive, first-generation RAF inhibitors (vemurafenib/PLX4720, RAFi) cause paradoxical activation of the MAPK pathway in BRAF-fusion tumors, inhibition can be achieved with 'paradox breaker' RAFi, such as PLX8394. Here we report that, unlike BRAF fusions, CRAF fusions are unresponsive to both generations of RAFi, vemurafenib and PLX8394, highlighting a distinct responsiveness of CRAF fusions to clinically relevant RAFi. Whereas PLX8394 decreased BRAF-fusion dimerization, CRAF-fusion dimerization is unaffected primarily because of robust protein-protein interactions mediated by the N-terminal non-kinase fusion partner, such as QKI. The pan-RAF dimer inhibitor, LY3009120, could suppress CRAF-fusion oncogenicity by inhibiting dimer-mediated signaling. In addition, as CRAF fusions activate both the MAPK and PI3K/mTOR signaling pathways, we identify combinatorial inhibition of the MAPK/mTOR pathway as a potential therapeutic strategy for CRAF-fusion-driven tumors. Overall, we define a mechanistic distinction between PLGG-associated BRAF- and CRAF/RAF1 fusions in response to RAFi, highlighting the importance of molecularly classifying PLGG patients for targeted therapy. Furthermore, our study uncovers an important contribution of the non-kinase fusion partner to oncogenesis and potential therapeutic strategies against PLGG-associated CRAF fusions and possibly pan-cancer CRAF fusions.

Dataset Information

Novel MEIS1-NCOA2 Gene Fusions Define a Distinct Primitive Spindle Cell Sarcoma of the Kidney.

Publications

Novel MEIS1-NCOA2 Gene Fusions Define a Distinct Primitive Spindle Cell Sarcoma of the Kidney.

Similar Datasets

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