Genome-Wide Study Reveals Genetic Correlation Between Melanoma Subtypes

Data from a recent genome-wide association study (GWAS) looking at the genetic underpinnings of in situ and invasive melanoma show significant shared genetic architecture between the two. 

Researchers for the study used data from four population-based genetic cohorts, including the UK Biobank, FinnGen, QSkin, and Q-MEGA, aiming to determine whether germline genetic factors differentially influence the risk of in situ melanoma compared to invasive melanoma. The team identified six genome-wide significant loci associated with in situ melanoma and 18 loci with invasive melanoma. 

According to their analysis, there was a strong genetic correlation (r = 0.96) between the two melanoma classifications, suggesting a substantial overlap in genetic risk factors. Specific loci near IRF4, KLF4, and HULC showed a significantly larger effect on in situ melanoma, while the MC1R locus had a greater impact on invasive melanoma.

Heritability estimates were consistent between the two subtypes, (in situ melanoma heritability, 6.7% and invasive melanoma, 4.9%). Despite the similar heritability estimates, polygenic risk scores (PRS) suggested germline genetics may play a role in determining whether an individual develops in situ or invasive melanoma. Participants with a higher PRS were more likely to develop invasive melanoma.

"There is much shared genetic architecture between in situ melanoma and invasive melanoma," the authors wrote. "Despite indistinguishable heritability estimates between the melanoma classifications, PRS suggest germline genetics may influence whether a person gets in situ melanoma or invasive melanoma. PRS could potentially help stratify populations based on invasive melanoma risk, informing future screening programs without exacerbating the current burden of melanoma overdiagnosis."

Source: Ingold N, et al. JAMA Dermatology. 2024. Doi:10.1001/jamadermatol.2024.2601