During their lifetime about 8% of patients with single primary cutaneous melanoma (SPM) will develop multiple primary melanomas (MPM), which are associated with significantly higher mortality compared to patients with SPM. Based on the evidence that the immune system plays a role in regulating melanoma progression we explored whether germline genetic variants controlling the expression of immunomodulatory genes (immunomodulatory quantitative trait loci, eQTLs) discern risk of MPM compared to patients with SPM or healthy controls.
Previously, we identified 50 eQTLs significantly associated with the expression of 265 immunomodulatory genes using the MuTHer twin cohort. These 50 SNPs were genotyped in 837 SPM and 104 MPM individuals using MassARRAY system. 1047 healthy controls were obtained from a publically available GWAS on CM ascertained at MD Anderson (phs000187.v1.p1). We employed multivariate logistic regression to test the association of SNPs with MPM vs cancer-free controls and MPM vs SPM.
When comparing MPM vs SPM, rs2071304, previously linked to expression of SPI1 in MuTHer data, showed a strong association with reduction of MPM risk (OR = 0.60; 95% CI = 0.45-0.81; p = 0.0007). Intriguingly, this variant also trended toward significance when comparing MPM vs controls (OR = 0.61; 95% CI: 0.44-0.85; p = 0.003). Finally, our most significant association when comparing MPM to controls was for rs2276645 (OR = 0.60; 95% CI = 0.45-0.81; p = 0.0008), an eQTL associated with Zap-70 expression.
Our data, for the first time, indicate that the inherited host immunity impacts risk of MPM in individuals with SPM, highlighting an importance of immune involvement in melanoma progression. The MPM risk-predicting genetic variants identified here or in expanded efforts, currently underway, may eventually lead to a diagnostic tool allowing for enhanced screening and clinical management of patients at risk of MPM, hence reducing elevated MPM-associated mortality. Additionally, our results further support that MPM and SPM may have different genetics underpinnings and should be treated as separate clinical entities.
Clinical trial identification
Legal entity responsible for the study
D. Polsky: Research grant: BioRad-laboratory reagents: Novartis. All other authors have declared no conflicts of interest.