Clonal hematopoiesis is enriched in melanoma and associated with genotype-specific differences in tumor growth and survival
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Background
The clinical significance of clonal hematopoiesis of indeterminate potential (CHIP) in melanoma remains incompletely defined, particularly with respect to CHIP genotype, clone size, and somatic mutations (e.g BRAF mutations). We integrated human cohort data and a syngeneic melanoma mouse model to evaluate whether CHIP is associated with melanoma risk, tumor growth, and differential clinical outcomes.
Methods
We analyzed CHIP prevalence and survival in a large treatment-unselected melanoma cohort (n=2,480), evaluated tumor growth in a syngeneic BRAF -mutant ( BRAF mut ) melanoma murine model of TET2 -CHIP and DNMT3A -CHIP, and assessed survival outcomes in an immune checkpoint inhibitor (ICI)-treated advanced melanoma cohort (n=361). Associations with progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier analyses and multivariable Cox proportional hazards models.
Results
CHIP was enriched among patients with treatment-unselected melanoma compared with age/sex-matched healthy controls, and larger CHIP clone size showed an age-adjusted association with inferior OS. In a syngeneic BRAF mut melanoma murine model, TET2 -CHIP, but not DNMT3A -CHIP, was associated with significantly increased primary melanoma tumor growth. Among patients with ICI-treated advanced melanoma, CHIP was associated with worse OS compared with patients without CHIP. TET2 -CHIP had the strongest adverse association with survival, whereas DNMT3A -CHIP was not significantly associated with PFS or OS.
Conclusions
CHIP is enriched in melanoma and exploratory analyses demonstrate genotype-specific differences in melanoma tumor growth and clinical outcomes. These findings support further investigation of genotype-specific CHIP profiling as a potential biomarker for melanoma risk stratification and immunotherapy outcomes.
What is already known on this topic
Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated condition linked to inflammation, cardiovascular disease, hematologic malignancy, and adverse outcomes across several cancer settings. Prior studies have suggested that CHIP may influence immune function and response to immune checkpoint inhibitors, but the clinical relevance of CHIP in melanoma, particularly by CHIP genotype, clone size, and tumor BRAF genotype, remains incompletely defined.
What this study adds
This study shows that CHIP is enriched among patients with melanoma and that larger CHIP clone size is associated with inferior overall survival in age-adjusted analyses. In complementary murine and clinical cohorts, TET2 -CHIP, but not DNMT3A -CHIP, was associated with increased melanoma tumor growth and worse survival outcomes among patients with ICI-treated advanced melanoma, with exploratory evidence that CHIP-associated risk may be most pronounced in BRAF -mutant melanoma.
How this study might affect research, practice or policy
These findings support further investigation of CHIP as a genotype-specific biomarker of melanoma biology that has the potential to refine risk stratification for patients with advanced melanoma. They further motivate mechanistic studies of how hematopoietic mutations shape antitumor immunity in specific tumor genomic contexts.
