Association of chemokine and chemokine receptor gene variants with occurrence of multiple primary melanoma
Chemokine (CK) and chemokine receptors (CKR) regulate cell growth, tumor immunity, migration, angiogenesis, and metastasis. We evaluated associations of inherited CK/CKR variants with subsequent primary melanomas among patients with a previous melanoma. Our population-based cohort included 2,458 incident single primary and 1,205 multiple primary melanoma (MPM) cases. We examined 215 a priori candidate polymorphisms selected based on prior evidence and predicted functional relevance, along with nine haplotype blocks. Logistic regression estimated odds ratios and 95% confidence intervals, adjusting for age at diagnosis, sex, age by sex interaction, and study center. Thirty variants across fourteen genes were nominally associated with MPM (p<0.05), with effect sizes ranging from 16% to 80%. Five haplotypes in CXCL12, CCL18, CXCR2, and CCR9 were significantly associated with MPM (pglobal<0.03) with stronger effects than individual effect-alleles. Functional annotation identified 160 associated index variants and linkage disequilibrium (LD) proxies acting as skin expression Quantitative Trait Loci (eQTLs) for CXCR2, XCR1, BCL9L, FYCO1, PNKD, RUFY4, and RP11–378A13.1 (p-value <1.06E-05 to 4.3E-34). These variants were classified functionally as candidate causal variants based on convergent regulatory annotation and skin-specific eQTL evidence, linking CK/CKR variants and haplotypes to downstream genes involved in epithelial–mesenchymal–like transition, matrix remodeling, and other tumorigenic processes, thereby implicating immune regulatory mechanisms in melanoma development. To our knowledge, this is the first study to demonstrate an association of a priori CK/CKR variants with subsequent melanoma risk. Validation and evaluation of associations with tumor characteristics and survival are warranted.