Abstract 870: Candidate SNPs in angiogenesis and lymphangiogenesis and risk of cutaneous melanoma

Abstract

Abstract Background: Currently, a combination of clinical and pathologic features are used to predict patient outcome in localized melanoma including age, sex, and tumor location, ulceration and Breslow depth. The presence or absence of metastasis in the local draining (sentinel) lymph node (SLN) as determined by SLN biopsy is considered the most accurate method for staging localized melanoma and is the most important predictor of recurrence and survival in patients with clinically node-negative melanoma. Additional biomarkers are needed to improve prediction models and target therapies to individual patients. Among the most promising candidate biomarkers are genes affecting lymph/angiogenesis which are thought to play a critical role in the development and progression of melanoma. We investigated whether single nucleotide polymorphisms (SNPs) in the lymph/angiogenesis pathway are associated with risk of SLN metastasis and mortality in patients with invasive melanoma of the skin. Methods: We examined risk of SLN metastasis and melanoma-related death in relation to 290 candidate and tagging SNPs in 26 lymph/angiogenesis genes in patients referred to the Moffitt Cancer Center between 1999 and 2008 for wide local excision and SLN staging of a primary invasive melanoma of the skin. Genotypes by the Illumina Goldengates in lymph/angiogenesis pathway genes were compared in a total of 177 patients with pathologically documented SLN metastasis and 375 patients negative for nodal metastasis, of whom a total of 41 (23%) and 19 (5%) patients, respectively, died from systemic disease. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the risk of SLN metastasis in relation to examined genotypes adjusting for age and gender. Proportional hazards regression was used to estimate age and gender-adjusted hazard ratios (HR) for melanoma-related death. Results: A total of 17 variant alleles in 8 lymph/angiogenesis genes including COL18A1, ELAVL1, FLT1, HSPG2, PDGFD, PIK3CA, NFRSF1b and VEGFA were associated with presence of SLN metastasis. An additional 17 SNPs in 10 genes including 4 genes associated with SLN metastasis (COL18A1, ELAVL1, PDGFD, PIK3CA), CXCL12, EGFR, FGFR4, IL10, NOS3, and PDPN were associated with survival. Carriers of the variant allele in COL18A1 rs728142 (minor allele frequency: 25%) were at increased risk of SLN metastasis (per allele OR: 1.33; 95% CI: 1.00-1.77; p trend =0.05) and melanoma-related death (per allele HR: 1.57; 95% CI: 1.06-2.33; p trend =0.03). Conclusion: Results from this exploratory analysis suggest that genetic variation in the lymphangiogenesis pathway may influence melanoma aggressiveness and patient outcome. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 870. doi:10.1158/1538-7445.AM2011-870