Research Article Gene Variants in Angiogenesis and Lymphangiogenesis and Cutaneous Melanoma Progression

Background: Angiogenesis and lymphangiogenesis are important in the progression of melanoma. We investigated associations between genetic variants in these pathways with sentinel lymph node (SLN) metastasis and mortality in 2 independent series of patients with melanoma. Methods: Participants at Moffitt Cancer Center were 552 patients, all Caucasian, with primary cutaneous melanoma referred for SLN biopsy. A total of 177 patients had SLN metastasis, among whom 60 died from melanoma. Associations between 238 single-nucleotide polymorphisms (SNP) in 26 genes and SLNmetastasis were estimated as ORs and 95 % confidence intervals (CI) using logistic regression. Competing risk regression wasused to estimateHRs and95%CI for each SNPandmelanoma-specificmortality.Weattempted to replicate significant findings using data from a genome-wide association study comprising 1,115 patients with melanoma who were referred for SLN biopsy from MD Anderson Cancer Center (MDACC), among whom 189 patients had SLN metastasis and 92 patients died from melanoma. Results: In the Moffitt dataset, we observed significant associations in 18 SNPs with SLNmetastasis and 17 SNPs with mortality. Multiple SNPs in COL18A1, EGF receptor (EGFR), FLT1, interleukin (IL)-10, platelet-derived growth factorD (PDGFD), PIK3CA, and toll-like receptor (TLR)-3were associatedwith the risk of SLN metastasis and/or patient mortality. The MDACC data set replicated an association between mortality and rs2220377 in PDGFD. Furthermore, in a meta-analysis, 3 additional SNPs were significantly associated with SLN metastasis (EGFR rs723526 and TLR3 rs3775292) and melanoma-specific death (TLR3 rs7668666). Conclusions: These findings suggest that genetic variation in angiogenesis and lymphangiogenesis con-tributes to regional nodal metastasis and progression of melanoma. Impact: Additional research attempting to replicate these results is warranted. Cancer Epidemiol Biomarker