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Epidermal autophagy and beclin 1 regulator 1 and loricrin: a paradigm shift in the prognostication and stratification of the American Joint Committee on Cancer stage I melanomas

Lookup NU author(s): Dr Robert Ellis, Dr Diana Tang, Dr Batoul Nasr, Alison Greenwood, Dr Ashleigh McConnell, Maria Anagnostou, Madona Elias, Dr Stamatina Verykiou, Dr Dalvir Bajwa, Dr Tom Ewen, Professor Nick Reynolds, Dr Graeme Watson, Dr Jane Armstrong, Dr Joy Allen, Dr Marie Labus, Professor Penny Lovat

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Background - The updated American Joint Committee on Cancer (AJCC) staging criteria for melanoma remain unable to identify high‐risk stage I tumour subsets. Objectives - To determine the utility of epidermal autophagy and beclin 1 regulator 1 (AMBRA1)/loricrin (AMLo) expression as a prognostic biomarker for AJCC stage I cutaneous melanoma.Methods - Peritumoral AMBRA1 expression was evaluated in a retrospective discovery cohort of 76 AJCC stage I melanomas. AMLo expression was correlated with clinical outcomes up to 12 years in two independent powered, retrospective validation and qualification cohorts comprising 379 AJCC stage I melanomas.Results - Decreased AMBRA1 expression in the epidermis overlying primary melanomas in a discovery cohort of 76 AJCC stage I tumours was associated with a 7‐year disease‐free survival (DFS) rate of 81·5% vs. 100% survival with maintained AMBRA1 (P < 0·081). Following an immunohistochemistry protocol for semi‐quantitative analysis of AMLo, analysis was undertaken in validation (n = 218) and qualification cohorts (n = 161) of AJCC stage I melanomas. Combined cohort analysis revealed a DFS rate of 98·3% in the AMLo low‐risk group (n = 239) vs. 85·4% in the AMLo high‐risk cohort (n = 140; P < 0·001). Subcohort multivariate analysis revealed that an AMLo hazard ratio (HR) of 4·04 [95% confidence interval (CI) 1·69–9·66; P = 0·002] is a stronger predictor of DFS than Breslow depth (HR 2·97, 95% CI 0·93–9·56; P = 0·068) in stage IB patients.Conclusions - Loss of AMLo expression in the epidermis overlying primary AJCC stage I melanomas identifies high‐risk tumour subsets independently of Breslow depth.


Publication metadata

Author(s): Ellis R, Tang D, Nasr B, ClinRes M, Greenwood A, McConnell A, Anagnostou ME, Elias M, Verykiou S, Bajwa D, Ewen T, Reynolds NJ, Barrett P, Carling E, Watson G, Armstrong J, Allen AJ, Horswell S, Labus M, Lovat PE

Publication type: Article

Publication status: Published

Journal: British Journal of Dermatology

Year: 2019

Pages: epub ahead of print

Online publication date: 06/05/2019

Acceptance date: 24/04/2019

Date deposited: 30/04/2019

ISSN (print): 0007-0963

ISSN (electronic): 1365-2133

Publisher: Wiley

URL: https://doi.org/10.1111/bjd.18086

DOI: 10.1111/bjd.18086


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