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

Abstract

Summary 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.

Long‐term deaths from melanoma according to tumor thickness at diagnosis

“…There is interest in developing biomarkers that can accurately identify high‐risk early stage disease from low‐risk early stage disease, though many of these require validation in larger cohorts before they are ready for clinical implementation. Many of the biomarkers published to date have relied on cohorts with relatively short‐term outcome data, 16–18 while one study relies on 12‐year outcome data 19 . When validating biomarkers to risk stratify early stage disease, our analyses indicate that it is important to consider follow‐up to 20 years to capture most of the fatalities.…”

“…Many of the biomarkers published to date have relied on cohorts with relatively short-term outcome data, [16][17][18] while one study relies on 12-year outcome data. 19 When validating biomarkers to risk stratify early stage disease, our analyses indicate that it is important to consider follow-up to 20 years to capture most of the fatalities.…”

HPV sensitizes OPSCC cells to cisplatin-induced apoptosis by inhibiting autophagy through E7-mediated degradation of AMBRA1

“…The optimum cut-point was identified at an H-score of 140 with a sensitivity of 55% (95% CI 39.83% -69.29%), specificity of 62.79% (95% CI 47.86% -75.62%) and a likelihood ratio of 1.48. Binary scores of 0 for low-risk (H-score <140) and 1 for high-risk (H-score > or = to 140) were applied for further Kaplan-Meier survival curve analysis 15 Other variables assessed included age, sex, HPV status and AMBRA1 tumor positivity.…”

BNIP3L Is a New Autophagy Related Prognostic Biomarker for Melanoma Patients Treated With AGI-101H

“…Ellis et al (30) have observed increased expression of autophagy receptor p62 in early AJCC stage melanomas, which was subsequently decreased in advanced metastatic tumors. Decreased or even complete loss of AMBRA1 expression has been observed in the epidermis overlying AJCC stage I melanomas, but not in benign nevi (31) suggesting the prognostic potential of this marker. Another study has shown that loss of Atg7 prevents melanoma development in BrafV600E mutant mice with allelic loss of Pten gene (32).…”