ROR1 and ROR2 expression in pancreatic cancer
Authors: Liu Dongli , Sharbeen George , Phillips Phoebe ,   Australian Pancreatic Cancer Genome Initiative, Johns Amber L. , Gill Anthony J. , Chantrill Lorraine A. , Timpson Paul , Chou Angela , Pajic Marina , Dwarte Tanya , Herrmann David , Vennin Claire , Cox Thomas R. , Pereira Brooke , Ritchie Shona , Reed Daniel A. , Chambers Cecilia R. , Metcalf Xanthe , Nobis Max , Waddell Nicola , Pearson John V. , Patch Ann-Marie , Nones Katia , Newell Felicity , Mukhopadhyay Pamela , Addala Venkateswar , Kazakoff Stephen , Holmes Oliver , Leonard Conrad , Wood Scott , Grimmond Sean M. , Hofmann Oliver , Samra Jaswinder S. , Pavlakis Nick , Arena Jennifer , High Hilda A. , Asghari Ray , Merrett Neil D. , Das Amitabha , Cosman Peter H. , Ismail Kasim , Stoita Alina , Williams David , Spigellman Allan , Lam Vincent W. , McLeod Duncan , Kirk Judy , Kench James G. , Grimison Peter , Sandroussi Charbel , Goodwin Annabel , Mead R. Scott , Tucker Katherine , Andrews Lesley , Texler Michael , Forrest Cindy , Ballal Mo , Fletcher David , Beilin Maria , Feeney Kynan , Epari Krishna , Mukhedkar Sanjay , Zeps Nikolajs , Nguyen Nan Q. , Ruszkiewicz Andrew R. , Worthley Chris , Chen John , Brooke-Smith Mark E. , Papangelis Virginia , Clouston Andrew D. , Barbour Andrew P. , O’Rourke Thomas J. , Fawcett Jonathan W. , Slater Kellee , Hatzifotis Michael , Hodgkinson Peter , Nikfarjam Mehrdad , Eshleman James R. , Hruban Ralph H. , Wolfgang Christopher L. , Scarpa Aldo , Lawlor Rita T. , Corbo Vincenzo , Bassi Claudio , Biankin Andrew V. , Jamieson Nigel B. , Chang David K. , Dreyer Stephan B. , Ford Caroline E. 
Published: November 2021

Abstract
Background
The Wnt receptors ROR1 and ROR2 are generating increased interest as cancer therapeutic targets but remain understudied in pancreatic ductal adenocarcinoma (PDAC). Compared to canonical Wnt/ β-catenin signalling, the role of noncanonical Wnt signalling in PDAC remains largely unknown. Only one study has investigated the prognostic significance of the noncanonical Wnt signalling receptor, ROR2 in PDAC. No studies have investigated the prognostic role of ROR1 in PDAC.

Methods
Here, we performed analysis of ROR1 and ROR2 mRNA expression in three publicly available datasets ICGC-PACA-AU (n = 81), TCGA-PAAD (n = 150) and CPTAC-PDAC (n = 137). ROR1 and ROR2 protein expression from the CPTAC-PDAC discovery cohort were also analysed. Immunohistochemistry (IHC) using the validated anti ROR1 monoclonal antibody (4A5) was performed on the Australian Pancreatic Cancer Genome Initiative (APGI) cohort of PDAC samples (n = 152). Association between ROR1 cytoplasmic staining intensity and clinicopathological parameters including stage, grade and overall survival (OS) was investigated.

Results
High ROR1 mRNA expression levels correlated with a favourable OS outcome in all of the ICGC-PACA-AU, TCGA-PAAD and CPTAC-PDAC cohorts. ROR1 protein expression was not associated with stage, grade or OS in the APGI cohort.

Conclusion
ROR1 and ROR2 have potential as prognostic markers when measured at the mRNA level in PDAC. Our IHC cohort did not support ROR1 protein expression in predicting OS, and highlighted the discrepancy of prognostic biomarkers when measured by MS, IHC and RNAseq.