Abstract LB129: Analysis of KRAS wildtype pancreatic ductal adenocarcinoma reveals mutation and expression-based similarities to cholangiocarcinoma

Abstract

Abstract Introduction Oncogenic KRAS mutations are absent in 10% of patients with pancreatic ductal adenocarcinoma (PDAC) and may represent a subgroup of PDAC with therapy options beyond standard-of-care chemotherapy. While distinct gene fusions have been implicated in KRAS wildtype (wt) PDAC, other traits unique to KRAS wt PDAC remain unexplored. Methods Patients with treatment-naive metastatic PDAC (n=63) received matched tumor/normal whole-genome and RNA sequencing and clinical follow-up as part of the PanGen trial (NCT02869802). Clinical data and mutation, gene fusion and copy alteration frequency was compared between KRAS wt (n=9) and mutant (n=54) groups. Metastatic colorectal adenocarcinoma and cholangiocarcinoma samples from the POG trial (NCT02155621) were incorporated for sequencing-based comparison. Results KRAS wt tumors showed lower frequency of TP53 SNV/indels (p=0.01) and distinct amplifications affecting chr1q genes NR5A2 (p=9.0e-4), MPC2 (p=0.002) and MCL1 (p=0.02) and chr8q gene SQLE (p=0.02). Oncogenic fusions involving NRG1, FGFR2, NTRK2 or BRAF were unique to KRAS wt tumors (67% of samples; p=1e-6). KRAS wt tumors showed expression patterns indicative of cholangiocytes and, when clustered alongside other tumor types, formed a distinct cluster with cholangiocarcinoma samples. Conclusion These data provide the first identification of distinct chr1q/chr8q amplification events unique to KRAS wt PDAC while highlighting novel and striking molecular similarities to cholangiocarcinoma. Taken together, results of the PanGen trial generate new hypotheses relevant to therapeutic targeting of KRAS wt PDAC and rationale towards incorporating KRAS mutation status as part of routine clinical testing in PDAC. Citation Format: James Topham, Erica Tsang, Joanna Karasinska, Andrew Metcalfe, Hassan Ali, Steve Kalloger, Veronika Csizmok, Laura Williamson, Emma Titmuss, Hui-Li Wong, Richard Moore, Andrew Mungall, Jonathan Loree, Oliver Bathe, Patricia Tang, Rachel Goodwin, Janessa Laskin, Marco Marra, Steven Jones, David Schaeffer, Daniel Renouf. Analysis of KRAS wildtype pancreatic ductal adenocarcinoma reveals mutation and expression-based similarities to cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB129.