Integrative analysis of KRAS wildtype metastatic pancreatic ductal adenocarcinoma reveals mutation and expression-based similarities to cholangiocarcinoma
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Published:2022-10-08
Issue:1
Volume:13
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Topham James T., Tsang Erica S., Karasinska Joanna M., Metcalfe AndrewORCID, Ali HassanORCID, Kalloger Steve E., Csizmok Veronika, Williamson Laura M., Titmuss EmmaORCID, Nielsen Karina, Negri Gian LucaORCID, Spencer Miko Sandra E.ORCID, Jang Gun Ho, Denroche Robert E., Wong Hui-li, O’Kane Grainne M.ORCID, Moore Richard A., Mungall Andrew J.ORCID, Loree Jonathan M.ORCID, Notta Faiyaz, Wilson Julie M.ORCID, Bathe Oliver F., Tang Patricia A., Goodwin Rachel, Morin Gregg B.ORCID, Knox Jennifer J., Gallinger Steven, Laskin Janessa, Marra Marco A.ORCID, Jones Steven J. M.ORCID, Schaeffer David F., Renouf Daniel J.ORCID
Abstract
AbstractOncogenic KRAS mutations are absent in approximately 10% of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) and may represent a subgroup of mPDAC with therapeutic options beyond standard-of-care cytotoxic chemotherapy. While distinct gene fusions have been implicated in KRAS wildtype mPDAC, information regarding other types of mutations remain limited, and gene expression patterns associated with KRAS wildtype mPDAC have not been reported. Here, we leverage sequencing data from the PanGen trial to perform comprehensive characterization of the molecular landscape of KRAS wildtype mPDAC and reveal increased frequency of chr1q amplification encompassing transcription factors PROX1 and NR5A2. By leveraging data from colorectal adenocarcinoma and cholangiocarcinoma samples, we highlight similarities between cholangiocarcinoma and KRAS wildtype mPDAC involving both mutation and expression-based signatures and validate these findings using an independent dataset. These data further establish KRAS wildtype mPDAC as a unique molecular entity, with therapeutic opportunities extending beyond gene fusion events.
Funder
Terry Fox Research Institute
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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