A relative methylation ordering biomarker of lactylation-related genes predicts prognosis and therapeutic response in cutaneous melanoma.
This study indicates that lactylation-related methylation patterns may help stratify cutaneous melanoma patients into high- and low-risk groups, potentially informing treatment strategies.
Where it sits
this study against the rest of the b7-33 (relaxin) corpusSummary and findings
This study developed a lactylation-related prognostic model for cutaneous melanoma using relative methylation orderings from The Cancer Genome Atlas melanoma cohort (n=458) and validated it in two additional cohorts (n=241). The model identified significant survival differences between high- and low-risk groups based on 1,743 locus pairs associated with overall survival. The findings suggest distinct immunological profiles and therapy sensitivities based on risk stratification.
Abstract
Cutaneous melanoma (CM) is highly invasive with limited prognostic tools, and the prognostic relevance of lactylation, a novel post-translational modification, remains unexplored. We developed a lactylation-related prognostic model using relative methylation orderings from The Cancer Genome Atlas (TCGA) melanoma cohort (<i>n</i> = 458), which was validated in two dependent cohorts (<i>n</i> = 241). Comprehensive analyses of immune infiltration, therapy efficacy, drug sensitivity, and tumour mutation burden were conducted between high- and low-risk groups. Results showed that 284 lactylation-related genes collected classified TCGA melanoma patients into two clusters with significant survival differences (Kaplan-Meier log-rank test, <i>p</i> = 0.046). Between the two clusters, 279 differentially methylated loci were identified (false discovery rate < 0.05 and |Δβ| >0.1). Based on these loci, 1,743 locus pairs were significantly associated with overall survival (Univariate Cox regression, false discovery rate < 0.05). From these significant pairs, the CM 11 locus-pair prognostic model (CM-LP11) consisting of 11 pairs was constructed, which could effectively stratify patients into high- and low-risk groups with significantly different overall survival across all datasets (all <i>p</i> < 0.05, log-rank test). The high-risk group exhibited an immunosuppressive microenvironment with reduced CD8+ T cells and B cells and increased monocytes (<i>p</i> < 0.05, Wilcoxon test). Functional analysis of methylation differences between risk groups showed significant immune response-related pathways such as antigen processing and presentation. The high- and low-risk patients also exhibited distinct sensitivity to cytotoxic chemotherapy, targeted therapy, and immunotherapy, with the low-risk group showing higher immunophenoscore, cytolytic activity, and tumor mutational burden. CM-LP11 represents a robust lactylation-related prognostic biomarker that predictive survival outcomes and therapeutic responses in CM patients, proving insights for personalized treatment strategies.
Background
This paper addresses the prognostic relevance of lactylation in cutaneous melanoma, a condition known for its invasiveness and poor prognostic tools. Prior research has not explored lactylation as a post-translational modification in this context. Understanding lactylation's role could enhance prognostic models and treatment strategies for melanoma patients.
Methods
The study utilized a retrospective analysis of the TCGA melanoma cohort (n=458) and validated findings in two additional cohorts (n=241). It focused on relative methylation orderings to develop a prognostic model. Primary outcomes included overall survival differences and immune infiltration analyses between identified high- and low-risk groups.
Results
The primary endpoint revealed significant survival differences between high- and low-risk groups, with a Kaplan-Meier log-rank test result of p=0.046. The analysis identified 279 differentially methylated loci, and 1,743 locus pairs were significantly associated with overall survival. The high-risk group showed an immunosuppressive microenvironment with significant alterations in immune cell populations.
Interpretation
The findings suggest that lactylation-related methylation patterns can stratify melanoma patients effectively, although the clinical significance of the identified differences in immune profiles and therapy responses requires further investigation. The study's reliance on retrospective data and potential confounding factors limits the strength of the conclusions drawn.
Key findings
- Kaplan-Meier log-rank test, p=0.046 for survival differences between clusters.
- 279 differentially methylated loci identified (false discovery rate < 0.05 and |Δβ| > 0.1).
- 1,743 locus pairs significantly associated with overall survival (Univariate Cox regression, false discovery rate < 0.05).
- All datasets showed significant differences in overall survival between high- and low-risk groups (all p < 0.05, log-rank test).
- High-risk group exhibited reduced CD8+ T cells and B cells, increased monocytes (p < 0.05, Wilcoxon test).
Limitations
- Retrospective analysis may not establish causation.
- Validation cohorts may not represent the broader melanoma population.
- Dependent on data from The Cancer Genome Atlas.
- Short follow-up duration for assessing long-term outcomes.