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. 2019 Jul 15;9(1):10173.
doi: 10.1038/s41598-019-46665-z.

Immunomodulatory germline variation associated with the development of multiple primary melanoma (MPM)

Robert Ferguson  1   2   3 , Alexi Archambault  1   2   3 , Danny Simpson  1   2   3 , Leah Morales  1   2   3 , Vylyny Chat  1   2   3 , Esther Kazlow  1   2   3 , Rebecca Lax  1   2   3 , Garrett Yoon  1   2   3 , Una Moran  1   3   4   5 , Richard Shapiro  3   6 , Anna Pavlick  3   4 , David Polsky  1   3   5   7 , Iman Osman  1   3   4   5 , Tomas Kirchhoff  8   9   10
Affiliations

Immunomodulatory germline variation associated with the development of multiple primary melanoma (MPM)

Robert Ferguson et al. Sci Rep. .

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.

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Conflict of interest statement

No conflict of interest, except for: David Polsky serves as a consultant at Novartis and MolecularMD and received research support from Novartis and Bio-Rad.

Figures

Figure 1
Figure 1
Genotype/gene expression correlation for the variants most significantly associated with MPM risk and MPM survival. The correlation between the genotype and gene expression level in LCLs along with the statistical significance (Linear mixed model p-value) were obtained from the MuTHER data. Each genotype was plotted, with reference allele genotypes on the right of each graph. rs2071304 (SPI1) (left plot) is associated with MPM risk and rs6695772 (BATF3) (right plot) is associated with survival.
Figure 2
Figure 2
Kaplan-Meier plot of overall survival by BATF3 genotypes. KM curves of MPM survival for rs6695772 (BATF3). The carriers of the alternate allele (C) show significantly worse OS. Survival curves were generated using univariate Kaplan-Meier estimates. P-values were estimated using log-rank test.
See this image and copyright information in PMC

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