| Autor: |
Prall, Owen W. J., Nastevski, Violeta, Xu, Huiling, McEvoy, Christopher R. E., Vissers, Joep H. A., Byrne, David J., Takano, Elena, Yerneni, Satwica, Ellis, Sarah, Green, Thomas, Mitchell, Catherine A., Murray, William K., Scott, Clare L., Grimmond, Sean M., Hofmann, Oliver, Papenfuss, Anthony, Kee, Damien, Fellowes, Andrew, Brown, Ian S., Miller, Gregory, Kumarasinghe, M. Priyanthi, Perren, Aurel, Nahm, Christopher B., Mittal, Anubhav, Samra, Jaswinder, Ahadi, Mahsa, Fox, Stephen B., Chou, Angela, Gill, Anthony J. |
| Zdroj: |
Modern Pathology; September 2020, Vol. 33 Issue: 9 p1811-1821, 11p |
| Abstrakt: |
There is now evidence that gene fusions activating the MAPK pathway are relatively common in pancreatic acinar cell carcinoma with potentially actionable BRAFor RETfusions being found in ~30%. We sought to investigate the incidence of RAF1fusions in pancreatic malignancies with acinar cell differentiation. FISH testing for RAF1was undertaken on 30 tumors comprising 25 ‘pure’ acinar cell carcinomas, 2 mixed pancreatic acinar-neuroendocrine carcinomas, 1 mixed acinar cell-low grade neuroendocrine tumor and 2 pancreatoblastomas. RAF1rearrangements were identified in 5 cases and confirmed by DNA and RNA sequencing to represent oncogenic fusions (GATM-RAF1, GOLGA4-RAF1, PDZRN3-RAF1, HERPUD1-RAF1and TRIM33-RAF1) and to be mutually exclusive with BRAFand RETfusions, as well as KRASmutations. Large genome-wide copy number changes were common and included 1q gain and/or 1p loss in all five RAF1FISH-positive acinar cell carcinomas. RAF1 expression by immunohistochemistry was found in 3 of 5 (60%) of fusion-positive cases and no FISH-negative cases. Phospho-ERK1/2 expression was found in 4 of 5 RAF1-fusion-positive cases. Expression of both RAF1 and phospho-ERK1/2 was heterogeneous and often only detected at the tumor-stroma interface, thus limiting their clinical utility. We conclude that RAF1gene rearrangements are relatively common in pancreatic acinar cell carcinomas (14.3% to 18.5% of cases) and can be effectively identified by FISH with follow up molecular testing. The combined results of several studies now indicate that BRAF, RETor RAF1fusions occur in between one third and one-half of these tumors but are extremely rare in other pancreatic malignancies. As these fusions are potentially actionable with currently available therapies, a strong argument can be made to perform FISH or molecular testing on all pancreatic acinar cell carcinomas. |
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