Dataset Information

Integrative analysis of KRAS wildtype metastatic pancreatic ductal adenocarcinoma reveals mutation and expression-based similarities to cholangiocarcinoma

ABSTRACT: Oncogenic 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 novel 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.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Gian Luca Negri

LAB HEAD: Gregg Morin

PROVIDER: PXD036632 | Pride | 2022-10-15

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20210705_Eclipse_SS_EPPIC_PDAC_B1F1.mzML	Mzml
	20210705_Eclipse_SS_EPPIC_PDAC_B1F10.mzML	Mzml
	20210705_Eclipse_SS_EPPIC_PDAC_B1F11.mzML	Mzml
	20210705_Eclipse_SS_EPPIC_PDAC_B1F12_redo.mzML	Mzml
	20210705_Eclipse_SS_EPPIC_PDAC_B1F3.mzML	Mzml

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Integrative analysis of KRAS wildtype metastatic pancreatic ductal adenocarcinoma reveals mutation and expression-based similarities to cholangiocarcinoma.

Topham James T JT Tsang Erica S ES Karasinska Joanna M JM Metcalfe Andrew A Ali Hassan H Kalloger Steve E SE Csizmok Veronika V Williamson Laura M LM Titmuss Emma E Nielsen Karina K Negri Gian Luca GL Spencer Miko Sandra E SE Jang Gun Ho GH Denroche Robert E RE Wong Hui-Li HL O'Kane Grainne M GM Moore Richard A RA Mungall Andrew J AJ Loree Jonathan M JM Notta Faiyaz F Wilson Julie M JM Bathe Oliver F OF Tang Patricia A PA Goodwin Rachel R Morin Gregg B GB Knox Jennifer J JJ Gallinger Steven S Laskin Janessa J Marra Marco A MA Jones Steven J M SJM Schaeffer David F DF Renouf Daniel J DJ

Nature communications 20221008 1

Oncogenic 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 ...[more]

PMID: 36209277

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Project description:Transcriptomic profiling Background Cholangiocarcinoma accounts for 5-10% of primary hepatic cancers. The etiology is unclear and patients are often diagnosed without risk factors. Resection is the only curative treatment although patients frequently remain undiagnosed until advanced stage of disease. Methods To construct molecular classification of cholangiocarcinoma, we profiled the transcriptomes of 104 freshly-frozen tumors and 59 matched non-cancerous livers obtained from Australia, Europe and the United States. We also performed mutational analysis of KRAS, EGFR and BRAF, and used laser-capture microdissection to obtain independent gene expression profiles for epithelial and stromal compartments in a subset of tumors. The selected target genes were validated by western blotting and immunohistochemistry. Results Transcriptomic profiling classified cholangiocarcinoma into two distinct subclasses defined by survival (P<0.0007) and early recurrence (P<0.001). Applying leave-one-out cross-validation, we optimized the prognostic classifier to 238 genes which were positively enriched in the epithelial tumor compartment. A deregulated HER2 network was associated with the epithelial compartment which also showed a frequent overexpression of Ki67, EGFR, MET and pRPS6 whereas inflammatory cytokines were enriched in tumor stroma specifically in patients with poor prognosis. KRAS mutations were found in 24.6% of patients with poor disease outcome. Conclusion Our study presents new insights into pathogenesis of cholangiocarcinoma and stratification of the patients according to survival and recurrence. Identification of a subgroup of patients among the poor prognostic cohort characterized by KRAS mutations and oncogenic-addiction may provide a novel therapeutic opportunity for this treatment-refractory malignancy. Profiling of individual cholangiocarcinomas and non-cancerous matched surrounding livers using normal bile ducts as reference