Abstract
Multiple primary melanoma (MPM) has been associated with a higher 10-year mortality risk compared to patients with single primary melanoma (SPM). Given that 3–8% of patients with SPM develop additional primary melanomas, new markers predictive of MPM risk are needed. Based on the evidence that the immune system may regulate melanoma progression, we explored whether germline genetic variants controlling the expression of 41 immunomodulatory genes modulate the risk of MPM compared to patients with SPM or healthy controls. By genotyping these 41 variants in 977 melanoma patients, we found that rs2071304, linked to the expression of SPI1, was strongly associated with MPM risk reduction (OR = 0.60; 95% CI = 0.45–0.81; p = 0.0007) when compared to patients with SPM. Furthermore, we showed that rs6695772, a variant affecting expression of BATF3, is also associated with MPM-specific survival (HR = 3.42; 95% CI = 1.57–7.42; p = 0.0019). These findings provide evidence that the genetic variation in immunomodulatory pathways may contribute to the development of secondary primary melanomas and also associates with MPM survival. The study suggests that inherited host immunity may play an important role in MPM development.
Highlights
3–8% of patients diagnosed with cutaneous melanoma will develop additional primary melanomas during their lifetime[1,2], which, may confer a higher 10-year mortality risk when compared to patients with a single primary melanoma (SPM)[3]
The study population stems from a cohort of patients with stage I-III cutaneous melanoma who were ascertained as part of The Interdisciplinary Melanoma Collaboration Group (IMCG) at NYU Langone Health, as previously described[24,25,26]
The patients with family history of melanoma were excluded from the analysis to reduce any confounding effects of known germline genetic factors associated with Multiple primary melanoma (MPM) or SPM development. 49.3% of patients were over 60 years of age and all patients were self-reported to be of European descent
Summary
3–8% of patients diagnosed with cutaneous melanoma will develop additional primary melanomas during their lifetime[1,2] (referred to as multiple primary melanoma, or MPM), which, may confer a higher 10-year mortality risk when compared to patients with a single primary melanoma (SPM)[3]. Studies on immunodeficient HIV patients with prior diagnoses of skin cancer have shown that these patients are at greater risk of skin cancer recurrence[9] These observations, and the fact that melanomas are more immunogenic compared to other tumors, further suggest that the host immunity may impact melanomagenesis both in the context of metastatic progression as well as in its initial presentation and recurrence, increasing a risk for additional primary melanomas. Other studies have examined associations between MPM risk and the pigmentation pathway by assessing variations in MC1R18–20 and MITF21, as well as vitamin D synthesis among individuals exposed to high levels of sunlight in recreational activities[22], these results were of borderline significance Besides these GWAS or candidate scans focused on genetic risk variation derived from predominantly SPM populations, the potentially novel MPM-specific risk loci have not been investigated. We have tested whether ieQTLs differentially modulate survival in patients with MPM
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