验证表皮AMBRA1和loricrin（AMBLor）作为美国癌症联合委员会非溃疡I/II期皮肤黑色素瘤预后生物标志物的作用。

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

作者信息

Ewen Tom, Husain Akhtar, Stefanos Niki, Barrett Paul, Jones Claire, Ness Tom, Long Anna, Horswell Stuart, Bosomworth Helen, Lowenstein Joe, Richardson Grant, Swan David, McConnell Ashleigh, Rose Aidan, Andrew Tom, Reynolds Nick, Malvehy Josep, Carrera Christina, Alos Llucia, Mailer Sonia, Helm Thomas, Ding Liang, Bogner Paul, Podlipnik Sebastian, Puig Susana, McArthur Grant A, Paragh Gyorgy, Labus Marie, Sloan Philip, Armstrong Jane L, Lovat Penny E

机构信息

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

Novo Path and Cellular Pathology.

出版信息

Br J Dermatol. 2024 Mar 15;190(4):549-558. doi: 10.1093/bjd/ljad459.

DOI:10.1093/bjd/ljad459

PMID:38006317

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.

摘要

背景

自噬调节蛋白AMBRA1（Beclin1调节的自噬激活分子）与终末分化标志物兜甲蛋白在I期黑色素瘤瘤周表皮中的联合表达可识别低转移风险的肿瘤亚群。

目的

验证瘤周AMBRA1和兜甲蛋白（AMBLor）的联合表达作为一种预后生物标志物，能够识别I期和II期黑色素瘤中肿瘤复发风险较低的患者。

方法

采用自动免疫组织化学法分析美国癌症联合委员会（AJCC）I期和II期非溃疡性黑色素瘤在不同地理位置的发现队列（n = 540）和验证队列（n = 300）中瘤周AMBRA1和兜甲蛋白的表达情况。分别对发现队列和验证队列以及合并后的队列中AMBLor状态与临床结局进行相关性分析。

结果

在发现队列中分析AMBLor发现，AMBLor低风险组的无复发生存率（RFS）为95.5%，而AMBLor风险组为81.7%（多因素对数秩检验，P < 0.001），阴性预测值（NPV）为96.0%。在验证队列中，AMBLor分析显示AMBLor低风险组的RFS率为97.6%，风险组为78.3%（多因素对数秩检验，P < 0.001），NPV为97.6%。在一个考虑AMBLor、Breslow厚度、年龄和性别的多因素模型中，对合并后的发现队列和验证队列进行分析显示，AMBLor的估计效应具有统计学意义，风险比为3.469（95%置信区间1.403 - 8.580，P = 0.007），总体NPV为96.5%。