Prolyl-4-hydroxylase ? subunit 2 (P4HA2) expression is a predictor of poor outcome in breast ductal carcinoma in situ (DCIS)

Toss, Michael S.; Miligy, Islam M.; Gorringe, Kylie L.; Alkawaz, Abdulbaqi; Khout, Hazem; Ellis, Ian O.; Green, Andrew R.; Rakha, Emad

Abstract

© 2018, Cancer Research UK. Background: Extracellular matrix (ECM) plays a crucial role in tumour behaviour. Prolyl-4-hydroxlase-A2 (P4HA2) is a key enzyme in ECM remodelling. This study aims to evaluate the prognostic significance of P4HA2 in breast ductal carcinoma in situ (DCIS). Methods: P4HA2 expression was assessed immunohistochemically in malignant cells and surrounding stroma of a large DCIS cohort comprising 481 pure DCIS and 196 mixed DCIS and invasive carcinomas. Outcome analysis was evaluated using local recurrence free interval (LRFI). Results: High P4HA2 expression was detected in malignant cells of half of pure DCIS whereas its expression in stroma was seen in 25% of cases. Higher P4HA2 expression was observed in mixed DCIS cases compared to pure DCIS both in tumour cells and in stroma. High P4HA2 was associated with features of high risk DCIS including younger age, higher grade, comedo necrosis, triple negative and HER2-positive phenotypes. Interaction between P4HA2 and radiotherapy was also observed regarding the outcome. High P4HA2 expression was an independent prognostic factor in predicting shorter LRFI. Conclusion: P4HA2 plays a role in DCIS progression and can potentially be used to predict DCIS outcome. Incorporation of P4HA2 with other clinicopathological parameters could refine DCIS risk stratification that can potentially guide management decisions.

Citation

Toss, M. S., Miligy, I. M., Gorringe, K. L., Alkawaz, A., Khout, H., Ellis, I. O., …Rakha, E. (2018). Prolyl-4-hydroxylase Α subunit 2 (P4HA2) expression is a predictor of poor outcome in breast ductal carcinoma in situ (DCIS). British Journal of Cancer, 119(12), 1518-1526. https://doi.org/10.1038/s41416-018-0337-x

• Journal Article Type: Article
• Acceptance Date: Oct 8, 2018
• Online Publication Date: Nov 9, 2018
• Publication Date: Dec 11, 2018
• Deposit Date: Nov 2, 2018
• Publicly Available Date: May 10, 2019
• Journal: British Journal of Cancer
• Print ISSN: 0007-0920
• Electronic ISSN: 1532-1827
• Publisher: Cancer Research UK
• Peer Reviewed: Peer Reviewed
• Volume: 119
• Issue: 12
• Pages: 1518-1526
• DOI: https://doi.org/10.1038/s41416-018-0337-x
• Keywords: DCIS, extracellular matrix, P4HA2, recurrence
• Public URL: https://nottingham-repository.worktribe.com/output/1221175
• Publisher URL: https://www.nature.com/articles/s41416-018-0337-x
• Additional Information: Received: 17 August 2018; Revised: 9 October 2018; Accepted: 25 October 2018; First Online: 9 November 2018; : The authors declare no competing interests.; : The datasets generated during and/or analysed during the current study are available from the corresponding authors on reasonable request.; : This research was supported and funded by the Egyptian Ministry of Higher Education and Scientific Research.; : This work obtained ethics approval by the North West – Greater Manchester Central Research Ethics Committee under the title; Nottingham Health Science Biobank (NHSB), reference number 15/NW/0685.; : This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).