Deciphering CHFR Role in Pancreatic Ductal Adenocarcinoma

Checkpoint with forkhead-associated and ring finger domains (CHFR) has been proposed as a predictive and prognosis biomarker for different tumor types, but its role in pancreatic ductal adenocarcinoma (PDAC) remains unknown. The aim of this study was two-pronged: to review the role of CHFR in PDAC and evaluating CHFR as a potential predictive biomarker in this disease. For this purpose, we first explored the CHFR messenger (m)RNA expression and promoter methylation through the TCGA database. Secondly, the CHFR expression and promoter methylation were prospectively evaluated in a cohort of patients diagnosed with borderline (n = 19) or resectable (n = 16) PDAC by immunohistochemistry (IHC), methylation specific-PCR (MSP), and pyrosequencing. The results from the TCGA database showed significant differences in terms of progression-free survival (PFS) and overall survival (OS) based on the CHFR mRNA expression, which was likely independent from the promoter methylation. Importantly, our results showed that in primarily resected patients and also the entire cohort, a higher CHFR expression as indicated by the higher IHC staining intensity might identify patients with longer disease-free survival (DFS) and OS, respectively. Similarly, in the same cohorts, patients with lower methylation levels by pyrosequencing showed significantly longer OS than patients without this pattern. Both, the CHFR expression intensity and its promoter methylation were established as independent prognostic factors for PFS and OS in the entire cohort. In contrast, no significant differences were found between different methylation patterns for CHFR and the response to taxane-based neoadjuvant treatment. These results suggest the potential role of the higher expression of CHFR and the methylation pattern of its promoter as potential prognostic biomarkers in PDAC, thus warranting further comprehensive studies to extend and confirm our preliminary findings.
This work was funded by grants from the Department of Health from the Government of Navarra (Ref. 008-2018), REFBIO II Pyrenees Biomedical Network from Programa INTERREG V-A España-Francia-Andorra (Ref. BMK_PANC) and Sociedad Española de Oncología Médica (SEOM) to AV. IG-B was supported by a predoctoral fellowship from the Department of Economic Development Government of Navarre Ayudas para la contratación de doctorandos y doctorandas por empresas y organismos de investigación y difusión de conocimientos: doctorados industriales 2018–2020. Intensification Programme Navarrabiomed 2017-2021 Obra Social La Caixa Fundación Caja Navarra. This work has also been supported by the Spanish Ministry of Economy [MINECO; BFU2016-80360-R (to JC)] and the Ministry of Science and Innovation [MICINN; PID2019- 105201RB-I00 (to JC)]. Instituto de Salud Carlos III, co-funded by European Union (ERDF/ESF, Investing in your future) [Predoctoral contract FI17/00282 (to EA-P)]. Junta de Andalucía (BIO-0139); GETNE2016 and GETNE2019 Research grants (to JC); and CIBERobn.