Melanoma is the most deadly skin cancer, with a worldwide incidence that increases year on year. A major unmet need is the discovery of means through which to identify patients with early stage melanoma at high risk of disease progression, meaning it will spread elsewhere in the body. This UK study aimed to determine if the loss of two proteins, AMBRA1 and loricrin, in the skin (upper layer of skin epidermis) overlying a melanoma is able to predict which patients are at risk of disease spread. Initially, levels of AMBRA1 were assessed in melanoma biopsies from 79 patients. Results suggested a reduction or loss of AMBRA1 in the overlying epidermis was associated with a higher risk of disease spread. The ability to predict the risk of melanoma progression was improved by measuring combined levels of epidermal loricrin and AMBRA1 (eAMLo). By studying a further 379 melanoma samples with at least 10 years of follow-up data (which shows what happened to the patient), the authors found that a stage I (early stage) melanoma in which eAMLo was lost was almost four times more likely to spread than a melanoma with maintained eAMLo. Importantly, patients in which eAMLo was retained (i.e. not lost) only had a 1.7% chance of disease progression. A melanoma's thickness is part of how its stage (progression) is measured, and currently, patients with a melanoma greater than 1mm thick are offered a further investigative test called sentinel lymph node biopsy (SLNB). However, a negative result from this invasive procedure does not provide any additional information about the chance of melanoma spread. Importantly, when eAMLo levels were assessed in melanomas eligible for SLNB, results further revealed eAMLo was better at identifying patients at truly low-risk of disease spread than SLNB alone. Collectively, this study shows that measuring eAMLo will help to show a patient's true risk of a melanoma progression, which will help to guide their ongoing treatment and monitoring. This summary relates to the study: Epidermal autophagy and beclin 1 regulator 1 and loricrin: a paradigm shift in the prognostication and stratificatee on Cancer stage I melanomas

黑色素瘤是最致命的皮肤癌, 全球发病率同比增长。主要未满足的需求是发现用于识别面临疾病进展高风险的早期黑色素瘤患者的方法, 这意味着它将传播到身体其他部位。 这项英国研究旨在确定在重叠黑色素瘤的皮肤上(皮肤表皮上层)的两种蛋白质 AMBRA1 和兜甲蛋白的缺失是否能够预测哪些患者存在疾病传播的风险。 最初, 在 79 例患者的黑色素瘤活检中评估了 AMBRA1 水平。结果表明 AMBRA1 在重叠表皮中减少或缺失与疾病传播风险更高相关。 通过测量表皮兜甲蛋白和 AMBRA1 (eAMLo) 的合并水平, 预测黑色素瘤进展风险的能力得到改善。 通过研究另外 379 个具有至少 10 年随访数据的黑色素瘤样本(显示患者发生的事件),作者发现 eAMLo 缺失的 I 期(早期)黑色素瘤的传播可能性比维持 eAMLo 水平的黑色素瘤多近四倍。 重要的是, eAMLo 保留(即未缺失)的患者只有 1.7% 的疾病进展几率。黑色素瘤的厚度是其分期(进展)测量方法的一部分, 目前还向大于 1 mm 厚的黑色素瘤患者提供进一步的研究性检查, 称为前哨淋巴结活检 (SLNB)。 然而, 这种侵入性操作的阴性结果并未提供有关黑色素瘤传播几率的任何其他信息。重要的是, 在符合 SLNB 资格的黑色素瘤中评估 eAMLo 水平时, 结果进一步显示 eAMLo 与单独的 SLNB 相比可更好地识别面临真正低疾病传播风险的患者。 总体而言,这项研究表明, 测量 eAMLo 将有助于显示患者真正的黑色素瘤进展风险, 这将帮助指导他们的持续治疗和监测。 This summary relates to the study: 表皮自噬和 beclin 1 调控基因 1 与兜甲蛋白:癌症 I 期黑色素瘤预测和分层的典范转移。

Despite revision of AJCC staging criteria, the identification and validation of credible prognostic biomarkers remains critical to identifying patients with high risk early stage melanomas, their subsequent counselling, stratification and follow up. Following the identification of AMBRA1 (a pro-autophagy regulatory protein) and Loricrin (a marker of terminal keratinocyte differentiation) as protein markers whose expression is lost in the epidermis overlying high risk primary AJCC stage I melanomas, the objective of the current study was to validate combined epidermal AMBRA1 and Loricrin (AMLo) as a prognostic biomarker for AJCC stage I melanoma. Semi quantitative automated immunohistochemical analysis of AMLo in 2 independent retrospective cohorts of 379 AJCC I melanomas revealed maintained expression correlated with 98.3% disease free survival (DFS) versus 85.5% for patients with AJCC stage I melanomas in which AMLo expression was lost. Sub-cohort, multivariate analysis revealed an AMLo hazard ratio of 4.04 (95% CI 1.69-9.66, P = 0.0017) as a stronger predictor of DFS than Breslow depth (multivariate analysis 2.97 (95% CI 0.925-9.56, P = 0.068) in AJCC stage IB patients. Moreover assessment of outcome in patients eligible for sentinel lymph-node biopsy revealed a post-test probability of metastasis of 18% in the AMLo high-risk group, while only 1% in the low-risk group, suggesting epidermal AMLo as a valuable pre-SLNB test. Collectively these data highlight epidermal AMLo as a novel prognostic marker for AJCC stage I melanoma; a simple IHC-based marker that can integrate seamlessly into standard clinical pathways of melanoma diagnostics, informing stratified follow-up (including appropriate SLNB use), reducing patient psychological burden, promoting better healthcare resource utilization and representing a major paradigm shift in melanoma management.

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.