Validation of epidermal AMBRA1 and loricrin (AMBLor) as a prognostic biomarker for nonulcerated American Joint Committee on Cancer stage I/II cutaneous melanoma

Author:

Ewen Tom1ORCID,Husain Akhtar2,Stefanos Niki3,Barrett Paul4,Jones Claire2,Ness Tom2,Long Anna2,Horswell Stuart15,Bosomworth Helen1,Lowenstein Joe16,Richardson Grant16,Swan David67,McConnell Ashleigh16,Rose Aidan1,Andrew Tom1,Reynolds Nick18,Malvehy Josep9,Carrera Christina9,Alos Llucia9,Mailer Sonia10,Helm Thomas1112,Ding Liang13,Bogner Paul1314,Podlipnik Sebastian9,Puig Susana9ORCID,McArthur Grant A10,Paragh Gyorgy14,Labus Marie16,Sloan Philip126,Armstrong Jane L67ORCID,Lovat Penny E16ORCID

Affiliation:

1. Translation and Clinical Research Institute, Newcastle University , Newcastle upon Tyne , UK

2. Novo Path and Cellular Pathology, Royal Victoria Infirmary , Newcastle upon Tyne , UK

3. Pathology, Addenbrookes Hospital, Cambridge University NHS Trust , Cambridge , UK

4. Pathology, University Hospitals of North Durham , Durham , UK

5. Francis Crick Institute , London , UK

6. AMLo Biosciences , Newcastle upon Tyne , UK

7. Faculty of Health Sciences and Wellbeing, University of Sunderland , Sunderland , UK

8. Department of Dermatology and NIHR Newcastle Biomedical Research Centre, Royal Victoria Infirmary , Newcastle upon Tyne , UK

9. Hospital Clinic Barcelona, University of Barcelona , Barcelona , Spain

10. Sir Peter MacCallum Department of Oncology, University of Melbourne , Melbourne, VIC , Australia

11. Division of Dermatology, Buffalo Medical Group , Williamsville, NY , USA

12. Department of Dermatology, Penn State Hershey , Hershey, Pennsylvania , USA

13. Department of Pathology, Roswell Park Comprehensive Cancer Center , Buffalo, NY , USA

14. Department of Dermatology, Roswell Park Comprehensive Cancer Center , Buffalo, NY , USA

Abstract

Abstract Background Combined expression of the autophagy-regulatory protein AMBRA1 (activating molecule in Beclin1-regulated autophagy) and the terminal differentiation marker loricrin in the peritumoral epidermis of stage I melanomas can identify tumour subsets at low risk of ­metastasis. Objectives To validate the combined expression of peritumoral AMBRA1 and loricrin (AMBLor) as a prognostic biomarker able to identify both stage I and II melanomas at low risk of tumour recurrence. Methods Automated immunohistochemistry was used to analyse peritumoral AMBRA1 and loricrin expression in geographically distinct discovery (n = 540) and validation (n = 300) cohorts of nonulcerated American Joint Committee on Cancer (AJCC) stage I and II melanomas. AMBLor status was correlated with clinical outcomes in the discovery and validation cohorts separately and combined. Results Analysis of AMBLor in the discovery cohort revealed a recurrence-free survival (RFS) rate of 95.5% in the AMBLor low-risk group vs. 81.7% in the AMBLor at-risk group (multivariate log-rank, P < 0.001) and a negative predictive value (NPV) of 96.0%. In the validation cohort, AMBLor analysis revealed a RFS rate of 97.6% in the AMBLor low-risk group vs. 78.3% in the at-risk group (multivariate log-rank, P < 0.001) and a NPV of 97.6%. In a multivariate model considering AMBLor, Breslow thickness, age and sex, analysis of the combined discovery and validation cohorts showed that the estimated effect of AMBLor was statistically significant, with a hazard ratio of 3.469 (95% confidence interval 1.403–8.580, P = 0.007) and an overall NPV of 96.5%. Conclusions These data provide further evidence validating AMBLor as a prognostic biomarker to identify nonulcerated AJCC stage I and II melanoma tumours at low risk of disease recurrence.

Funder

National Institute for Health Research

Invention for Innovation

AMLo

AMLo Biosciences Ltd

Publisher

Oxford University Press (OUP)

Subject

Dermatology

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