Abstract
To investigate whether genetic variants of platelet-derived growth factor (PDGF) signaling pathway genes are associated with survival of cutaneous melanoma (CM) patients, we assessed associations of single-nucleotide polymorphisms in PDGF pathway with melanoma-specific survival in 858 CM patients of M.D. Anderson Cancer Center (MDACC). Additional data of 409 cases from Harvard University were also included for further analysis. We identified 13 SNPs in four genes (COL6A3, NCK2, COL5A1 and PRKCD) with a nominal P < 0.05 and false discovery rate (FDR) < 0.2 in MDACC dataset. Based on linkage disequilibrium, functional prediction and minor allele frequency, a representative SNP in each gene was selected. In the meta-analysis using MDACC and Harvard datasets, there were two SNPs associated with poor survival of CM patients: rs6707820 C>T in NCK2 (HR = 1.87, 95% CI = 1.35-2.59, Pmeta = 1.53E-5); and rs2306574 T>C in PRKCD (HR = 1.73, 95% CI = 1.33-2.24, Pmeta = 4.56E-6). Moreover, CM patients in MDACC with combined risk genotypes of these two loci had markedly poorer survival (HR = 2.47, 95% CI = 1.58-3.84, P < 0.001). Genetic variants of rs6707820 C>T in NCK2 and rs2306574 T>C in PRKCD of the PDGF signaling pathway may be biomarkers for melanoma survival.
Highlights
Cutaneous melanoma (CM) is the most aggressive form of skin cancer
In the metaanalysis using M.D. Anderson Cancer Center (MDACC) and Harvard datasets, there were two single nucleotide polymorphism (SNP) associated with poor survival of cutaneous melanoma (CM) patients: rs6707820 C>T in NCK2 (HR = 1.87, 95% confident interval (CI) = 1.35-2.59, Pmeta = 1.53E-5); and rs2306574 T>C in PRKCD (HR = 1.73, 95% CI = 1.33-2.24, Pmeta = 4.56E-6)
A total of 48 CM-specific deaths were observed in the Harvard dataset, and only age was significantly associated with melanoma-specific survival (MSS) in the univariate analysis (Supplementary Table 1)
Summary
Cutaneous melanoma (CM) is the most aggressive form of skin cancer. Its incidence rates continuously increased in white men (2.1% per year) and women (2.4% per year) between 1999 and 2008 in the United States [1]. CM patients with thinner tumors have a longer survival than those with thicker tumors, and currently all patients with microscopic nodal metastases, regardless of the extent of tumor burden, are classified as stage III, including www.impactjournals.com/oncotarget micrometastases detected by immunohistochemistry [3]. These methods are not sufficient to accurately discriminate CM patients for personalized clinical assessment or prediction of their survival, and additional effective clinical or molecular characterization of CM patients with more accurate prognostic potential for personalized health care is needed [4, 5]. There is growing evidence for the role of genetic (germline) variants in CM prognosis [5], and genetic variant discovery may provide clues about the mechanisms underlying melanocyte carcinogenesis and CM progression, leading to improved prediction of CM prognosis
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