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http://purl.uniprot.org/citations/31056744http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/31056744http://www.w3.org/2000/01/rdf-schema#comment"

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. What's already known about this topic? There is an unmet clinical need for biomarkers of early-stage melanoma. Autophagy and beclin 1 regulator 1 (AMBRA1) is a proautophagy regulatory protein with known roles in cell proliferation and differentiation, and is a known tumour suppressor. Loricrin is a marker of epidermal terminal differentiation. What does this study add? AMBRA1 has a functional role in keratinocyte/epidermal proliferation and differentiation. The combined decrease/loss of peritumoral AMBRA1 and loricrin is associated with a significantly increased risk of metastatic spread in American Joint Committee on Cancer (AJCC) stage I tumours vs. melanomas, in which peritumoral AMBRA1 and loricrin are maintained, independently of Breslow depth. What is the translational message? The integration of peritumoral epidermal AMBRA1/loricrin biomarker expression into melanoma care guidelines will facilitate more accurate, personalized risk stratification for patients with AJCC stage I melanomas, thereby facilitating stratification for appropriate follow-up and informing postdiagnostic investigations, including sentinel lymph node biopsy, ultimately resulting in improved disease outcomes and rationalization of healthcare costs."xsd:string
http://purl.uniprot.org/citations/31056744http://purl.org/dc/terms/identifier"doi:10.1111/bjd.18086"xsd:string
http://purl.uniprot.org/citations/31056744http://purl.uniprot.org/core/author"Armstrong J."xsd:string
http://purl.uniprot.org/citations/31056744http://purl.uniprot.org/core/author"Elias M."xsd:string
http://purl.uniprot.org/citations/31056744http://purl.uniprot.org/core/author"Tang D."xsd:string
http://purl.uniprot.org/citations/31056744http://purl.uniprot.org/core/author"Greenwood A."xsd:string
http://purl.uniprot.org/citations/31056744http://purl.uniprot.org/core/author"Barrett P."xsd:string
http://purl.uniprot.org/citations/31056744http://purl.uniprot.org/core/author"Lovat P.E."xsd:string
http://purl.uniprot.org/citations/31056744http://purl.uniprot.org/core/author"Ellis R."xsd:string
http://purl.uniprot.org/citations/31056744http://purl.uniprot.org/core/author"McConnell A."xsd:string
http://purl.uniprot.org/citations/31056744http://purl.uniprot.org/core/author"Anagnostou M.E."xsd:string
http://purl.uniprot.org/citations/31056744http://purl.uniprot.org/core/author"Horswell S."xsd:string
http://purl.uniprot.org/citations/31056744http://purl.uniprot.org/core/author"Watson G."xsd:string
http://purl.uniprot.org/citations/31056744http://purl.uniprot.org/core/author"Reynolds N.J."xsd:string
http://purl.uniprot.org/citations/31056744http://purl.uniprot.org/core/author"Allen A.J."xsd:string
http://purl.uniprot.org/citations/31056744http://purl.uniprot.org/core/author"Nasr B."xsd:string
http://purl.uniprot.org/citations/31056744http://purl.uniprot.org/core/author"Bajwa D."xsd:string
http://purl.uniprot.org/citations/31056744http://purl.uniprot.org/core/author"Carling E."xsd:string
http://purl.uniprot.org/citations/31056744http://purl.uniprot.org/core/author"Ewen T."xsd:string
http://purl.uniprot.org/citations/31056744http://purl.uniprot.org/core/author"Labus M."xsd:string
http://purl.uniprot.org/citations/31056744http://purl.uniprot.org/core/author"Verykiou S."xsd:string
http://purl.uniprot.org/citations/31056744http://purl.uniprot.org/core/date"2020"xsd:gYear
http://purl.uniprot.org/citations/31056744http://purl.uniprot.org/core/name"Br J Dermatol"xsd:string
http://purl.uniprot.org/citations/31056744http://purl.uniprot.org/core/pages"156-165"xsd:string
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