From Spot to Spread: Decoding the Genetics Behind Melanoma’s In-situ to Invasive Evolution

Original Article: Exploring the Germline Genetics of In Situ and Invasive Cutaneous Melanoma A Genome-Wide Association Study Meta-Analysis

What are the key takeaways of this article?

Melanoma, a serious form of skin cancer, originates from melanocytes, the pigment-producing cells in the skin. It is primarily classified into two types: melanoma in situ and invasive melanoma. Melanoma in situ remains confined to the epidermis, while invasive melanoma extends into the dermis and has the potential to spread to other parts of the body. Recent research highlights that not all in situ lesions progress to invasive melanoma; many remain indolent. This underscores the importance of early detection, as the five-year survival rate for invasive melanoma ranges from 93% for stage 1 to 53% for stage 4.

Germline genetic variations are known to contribute to melanoma risk, with 55 genetic loci having been identified as associated with the disease. However, it remains unclear whether these genetic variations influence the risk of melanoma in situ differently from invasive melanoma. To address this gap, the study conducted three genome-wide association study (GWAS) meta-analyses: comparing in situ melanoma to controls, invasive melanoma to controls, and a case-case comparison of in situ versus invasive melanoma. Utilizing four population-based genetic cohorts, the study calculated genetic effect estimates for single-nucleotide variants (SNVs) across the genome. It also assessed SNV-based heritability, the genetic correlation between melanoma subtypes, and generated polygenic risk scores (PRS) for both in situ and invasive melanoma using the Q-MEGA cohort.

The meta-analysis identified 18 significant genetic loci associated with invasive melanoma and 6 associated with in situ melanoma. Among these, four loci (TERT, MTAP, MC1R, and ASIP) were significant for both melanoma types, while two loci (IRF4 and KLF4) were significant only for in situ melanoma, indicating a stronger influence on this subtype. The study found a strong correlation in effect estimates between in situ and invasive melanoma (r = 0.91 to 0.95) and similar heritability estimates for both types, with in situ melanoma having a heritability of 6.7% and invasive melanoma 4.9%. The genetic correlation between the two subtypes was 0.96. Furthermore, PRS analysis indicated that individuals with invasive melanoma had significantly higher PRS compared to those with in situ melanoma, with an odds ratio of 1.43 per standard deviation increase in PRS. The robustness of these PRS findings was confirmed even after the exclusion of specific SNVs. Additionally, the case-case GWAS meta-analysis of in situ versus invasive melanoma identified a genome-wide significant SNV on chromosome 6 (rs4566922). This SNV is located in a conserved noncoding region, suggesting potential functional relevance, although its exact role remains undefined.

In conclusion, the research indicates a substantial shared genetic component between in situ and invasive melanoma, with certain loci potentially influencing in situ melanoma more strongly (e.g., IRF4, KLF4) and others affecting invasive melanoma (e.g., MC1R, SLC45A2). The SNV rs4566922 may pinpoint a genomic region important for distinguishing between melanoma types, although its functional significance needs further investigation. Incorporating PRS could improve the specificity of melanoma screening programs by better predicting invasive cases without exacerbating overdiagnosis. Therefore, future studies should aim to replicate these findings and assess the feasibility of implementing targeted melanoma screening based on genetic risk factors.

Publication Date: October 3, 2024

Reference: Ingold N, Seviiri M, Ong JS, et al. Exploring the Germline Genetics of In Situ and Invasive Cutaneous Melanoma: A Genome-Wide Association Study Meta-Analysis. JAMA Dermatol. Published online August 14, 2024. doi:10.1001/jamadermatol.2024.2601

Summary By: Sascha Azoulay