Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
Duke Cancer Institute, Duke University Medical Center, Durham, NC, 27710, USA.
Br J Dermatol. 2020 Oct;183(4):719-728. doi: 10.1111/bjd.18878. Epub 2020 Feb 26.
Folate metabolism plays an important role in DNA methylation and nucleic acid synthesis and thus may function as a regulatory factor in cancer development. Genome-wide association studies (GWASs) have identified some single-nucleotide polymorphisms (SNPs) associated with cutaneous melanoma-specific survival (CMSS), but no SNPs were found in genes involved in the folate metabolic pathway.
To examine associations between SNPs in folate metabolic pathway genes and CMSS.
We comprehensively evaluated 2645 (422 genotyped and 2223 imputed) common SNPs in folate metabolic pathway genes from a published GWAS of 858 patients from The University of Texas MD Anderson Cancer Center and performed the validation in another GWAS of 409 patients from the Nurses' Health Study and Health Professionals Follow-up Study, in which 95/858 (11·1%) and 48/409 (11·7%) patients died of cutaneous melanoma, respectively.
We identified two independent SNPs (MTHFD1 rs1950902 G>A and ALPL rs10917006 C>T) to be associated with CMSS in both datasets, and their meta-analysis yielded an allelic hazards ratio of 1·75 (95% confidence interval 1·32-2·32, P = 9·96 × 10 ) and 2·05 (1·39-3·01, P = 2·84 × 10 ), respectively. The genotype-phenotype correlation analyses provided additional support for the biological plausibility of these two variants' roles in tumour progression, suggesting that variation in SNP-related mRNA expression levels is likely to be the mechanism underlying the observed associations with CMSS.
Two possibly functional genetic variants, MTHFD1 rs1950902 and ALPL rs10917006, were likely to be independently or jointly associated with CMSS, which may add to personalized treatment in the future, once further validated. What is already known about this topic? Existing data show that survival rates vary among patients with melanoma with similar clinical characteristics; therefore, it is necessary to identify additional complementary biomarkers for melanoma-specific prognosis. A hypothesis-driven approach, by pooling the effects of single-nucleotide polymorphisms (SNPs) in a specific biological pathway as genetic risk scores, may provide a prognostic utility, and genetic variants of genes in folate metabolism have been reported to be associated with cancer risk. What does this study add? Two genetic variants in the folate metabolic pathway genes, MTHFD1 rs1950902 and ALPL rs10917006, are significantly associated with cutaneous melanoma-specific survival (CMSS). What is the translational message? The identification of genetic variants will make a risk-prediction model possible for CMSS. The SNPs in the folate metabolic pathway genes, once validated in larger studies, may be useful in the personalized management and treatment of patients with cutaneous melanoma.
叶酸代谢在 DNA 甲基化和核酸合成中起着重要作用，因此可能是癌症发展的调节因子。全基因组关联研究（GWAS）已经确定了一些与皮肤黑色素瘤特异性生存（CMSS）相关的单核苷酸多态性（SNP），但在叶酸代谢途径基因中没有发现 SNP。
研究叶酸代谢途径基因中的 SNP 与 CMSS 之间的关联。
我们全面评估了来自德克萨斯大学 MD 安德森癌症中心 858 例患者 GWAS 的叶酸代谢途径中 2645 个（422 个已分型和 2223 个已推断）常见 SNP，并在另一项来自护士健康研究和健康专业人员随访研究的 409 例患者的 GWAS 中进行了验证，其中 95/858（11.1%）和 48/409（11.7%）患者死于皮肤黑色素瘤。
我们在两个数据集都发现了两个独立的 SNP（MTHFD1 rs1950902 G>A 和 ALPL rs10917006 C>T）与 CMSS 相关，它们的荟萃分析得出等位基因危险比为 1.75（95%置信区间 1.32-2.32，P=9.96×10）和 2.05（1.39-3.01，P=2.84×10）。基因型-表型相关性分析为这两个变体在肿瘤进展中的作用的生物学合理性提供了额外的支持，表明 SNP 相关 mRNA 表达水平的变化很可能是与 CMSS 观察到的关联的机制。
两个可能具有功能的遗传变异体，MTHFD1 rs1950902 和 ALPL rs10917006，可能独立或共同与 CMSS 相关，一旦进一步验证，这可能有助于未来的个体化治疗。关于这个主题已经知道什么？现有数据表明，具有相似临床特征的黑色素瘤患者的生存率存在差异；因此，有必要为黑色素瘤的特定预后确定其他补充生物标志物。通过将特定生物途径中单核苷酸多态性（SNP）的效应汇总为遗传风险评分，采用基于假设的方法可能具有预后效用，并且已经报道叶酸代谢基因的遗传变异与癌症风险相关。本研究增加了什么？叶酸代谢途径基因中的两个遗传变异体，MTHFD1 rs1950902 和 ALPL rs10917006，与皮肤黑色素瘤特异性生存（CMSS）显著相关。这有什么转化意义？遗传变异的鉴定将使 CMSS 的风险预测模型成为可能。叶酸代谢途径基因中的 SNP 一旦在更大的研究中得到验证，可能对皮肤黑色素瘤患者的个体化管理和治疗有用。
