Genetic variants in fanconi anemia pathway genes BRCA2 and FANCA predict melanoma survival

Abstract

Cutaneous melanoma (CM) is the most lethal skin cancer. The Fanconi anemia (FA) pathway involved in DNA crosslink repair may affect CM susceptibility and prognosis. Using data derived from published genome-wide association study, we comprehensively analyzed the associations of 2,339 common single-nucleotide polymorphisms (SNPs) in 14 autosomal FA genes with overall survival (OS) in 858 CM patients. By performing false-positive report probability corrections and stepwise Cox proportional hazards regression analyses, we identified significant associations between CM OS and four putatively functional SNPs: BRCA2 rs10492396 (AG vs. GG: adjusted hazard ratio (adjHR)=1.85, 95% confidence interval (CI)=1.16-2.95, P=0.010), rs206118 (CC vs. TT+TC: adjHR=2.44, 95% CI=1.27-4.67, P=0.007), rs3752447 (CC vs. TT+TC: adjHR=2.10, 95% CI=1.38-3.18, P=0.0005), and FANCA rs62068372 (TT vs. CC+CT: adjHR=1.85, 95% CI=1.27-2.69, P=0.001). Moreover, patients with an increasing number of unfavorable genotypes (NUG) of these loci had markedly reduced OS and melanoma-specific survival (MSS). The final model incorporating with NUG, tumor stage, and Breslow thickness showed an improved discriminatory ability to classify both 5-year OS and 5-year MSS. Additional investigations, preferably prospective studies, are needed to validate our findings.

Figure 1. Kaplan-Meier survival analysis

For CM OS (a) by 0, 1, 2, 3/4 NUG (i.e., rs10492396 AG, rs206118 CC, rs3752447 CC, rs62068372 TT) and (b) by 0-1 and 2-4 NUG; for CM MSS (c) by 0, 1, 2, 3/4 NUG and (d) by 0-1 and 2-4 NUG.

Figure 2. Receiver operating characteristic curves for prediction of CM survival

(a) 5-year OS rate and (b) 5-year MSS rate, based on tumor stage and thickness; tumor stage, Breslow thickness plus NUG.

Figure 3. Up-regulation of BRCA2 (a, b) and FANCA (c, d) in the progression of melanoma

The Y axis is a score representing the expression levels of BRCA2 and FANCA.

Figure 4. SNP-gene associations

Analyses of BRCA2 expression levels, by genotypes of (a) rs10492396, (b) rs206118, (c) rs3752447 and (d) combined risk genotypes (i.e., rs206118 CC, rs10492396 AG, rs3752447 CC) in 270 HapMap lymphoblastoid cell lines from all population. The number of individuals with missing data for rs10492396, rs206118 and combined risk genotypes were 2, 2 and 4, respectively. The Y axis is the normalized gene expression levels.