RAF1 rearrangements are common in pancreatic acinar cell carcinomas.

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; ... (2020). RAF1 rearrangements are common in pancreatic acinar cell carcinomas. Modern pathology, 33(9), pp. 1811-1821. Nature Publishing Group 10.1038/s41379-020-0545-9

[img] Text
1.99_RAF1_ACC.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.
© The Author(s), under exclusive licence to United States & Canadian Academy of Pathology 2020

Download (2MB) | Request a copy

There is now evidence that gene fusions activating the MAPK pathway are relatively common in pancreatic acinar cell carcinoma with potentially actionable BRAF or RET fusions being found in ~30%. We sought to investigate the incidence of RAF1 fusions in pancreatic malignancies with acinar cell differentiation. FISH testing for RAF1 was 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. RAF1 rearrangements were identified in 5 cases and confirmed by DNA and RNA sequencing to represent oncogenic fusions (GATM-RAF1, GOLGA4-RAF1, PDZRN3-RAF1, HERPUD1-RAF1 and TRIM33-RAF1) and to be mutually exclusive with BRAF and RET fusions, as well as KRAS mutations. Large genome-wide copy number changes were common and included 1q gain and/or 1p loss in all five RAF1 FISH-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 RAF1 gene 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, RET or RAF1 fusions 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.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Perren, Aurel


500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health




Nature Publishing Group




Aurel Perren

Date Deposited:

24 Sep 2020 19:30

Last Modified:

05 Dec 2022 15:40

Publisher DOI:


PubMed ID:






Actions (login required)

Edit item Edit item
Provide Feedback