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

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.

Review on Canine Oral Melanoma: An Undervalued Authentic Genetic Model of Human Oral Melanoma?

Oral melanoma (OM) is a highly aggressive tumor of the oral cavity in humans and dogs. Here we review the phenotypic similarities between the disease in these 2 species as the basis for the view that canine OM is a good model for the corresponding human disease. Utility of the "canine model" has likely been hindered by a paucity of information about the extent of the molecular genetic similarities between human and canine OMs. Current knowledge of the somatic alterations that underpin human tumorigenesis and metastatic progression is relatively limited, primarily due to the rarity of the disease in humans and consequent lack of opportunity for large-scale molecular analysis. The molecular genetic comparisons between human and canine OMs that have been completed indicate some overlap between the somatic mutation profiles of canine OMs and a subset of human OMs. However, further comparative studies featuring, in particular, larger numbers of human OMs are required to provide substantive evidence that canine OMs share mechanisms of tumorigenesis with at least a subset of human OMs. Future molecular genetic investigations of both human and canine OMs should investigate how primary tumors develop a metastatic gene expression signature and the genetic and epigenetic alterations specific to metastatic sites. Such studies may identify genetic alterations and pathways specific to the metastatic disease which could be targetable by new drugs.