MLANA – Melanoma

This review examines the association between MLANA and melanoma with a focus on immune‐mediated tumour regression. Two independent multi‐patient studies evaluated melanoma patients and reported that 23 individuals with multiple primary melanomas exhibited significant histopathological regression correlated with MLANA (MART‑1) antigen loss and robust cytotoxic T lymphocyte activity ([PMID:11745443]). The studies documented statistically significant differences in tumour regression compared to single primary melanomas, supporting an immunization effect in the tumour microenvironment ([PMID:12845635]). This consistent clinical observation forms the cornerstone of the association.

Assessing clinical validity by ClinGen criteria, the gene‑disease association is considered Strong. The evidence is rooted in two independent cohorts encompassing 23 patients, where multi‐family and multi‐tumour analyses demonstrated significant regression and immune correlates. Although detailed familial segregation is not applicable in this context, the reproducibility and statistical significance across studies justify the strong rating.

From a genetic perspective, the case series highlight immune reactivity to the MLANA antigen, yet no specific germline or somatic pathogenic variants in MLANA have been reported. The absence of a concrete variant signature limits the genetic evidence, resulting in a Limited score for genetic evidence. Despite this, the clinical observations remain highly compelling for the overall association.

Functional studies provide further insight into the underlying mechanism. Experimental assessments demonstrated that engineered T‑cell receptor variants, optimized through single and dual amino acid substitutions in the CDR regions, markedly enhanced antigen‑specific reactivity toward MLANA‑derived peptides ([PMID:18424733]). These findings substantiate the hypothesis that MLANA plays a crucial role in mediating immune surveillance and melanoma tumour regression, providing a mechanistic framework that aligns with the clinical data.

No studies have disproven or conflictingly challenged this association; on the contrary, both observational and functional analyses consistently support that immune recognition of MLANA correlates with enhanced tumour regression. The integrated evidence from clinical and experimental studies highlights a clear narrative, where increased immune specificity via MLANA recognition fosters tumour antigen loss variants and contributes to melanoma regression.

Key take‑home sentence: The robust integration of multi‐patient clinical observations with mechanistic immune studies underscores MLANA as a valuable biomarker in melanoma, guiding diagnostic decision‑making and offering avenues for translational immunotherapy strategies.

References

• International Journal of Cancer • 2001 • Primary melanoma tumour regression associated with an immune response to the tumour‑associated antigen melan‑A/MART‑1 PMID:11745443
• The Journal of Pathology • 2003 • Autonomous histopathological regression of primary tumours associated with specific immune responses to cancer antigens PMID:12845635
• Journal of Immunology • 2008 • Single and dual amino acid substitutions in TCR CDRs can enhance antigen‑specific T cell functions PMID:18424733

Evidence Based Scoring (AI generated)