Laboratory of Cancer Genetics, Faculty of Medical Sciences, University of Campinas, Campinas, São Paulo, Brazil.
Department of Statistics, Institute of Mathematics, Statistic, and Computer Science, University of Campinas, Campinas, São Paulo, Brazil.
Sci Rep. 2020 Jul 22;10(1):12129. doi: 10.1038/s41598-020-68945-9.
Ultraviolet light exposure and cutaneous pigmentation are important host risk factors for cutaneous melanoma (CM), and it is well known that inherited ability to produce melanin varies in humans. The study aimed to identify single-nucleotide variants (SNVs) on pigmentation-related genes with importance in risk and clinicopathological aspects of CM. The study was conducted in two stages. In stage 1, 103 CM patients and 103 controls were analyzed using Genome-Wide Human SNV Arrays in order to identify SNVs in pigmentation-related genes, and the most important SNVs were selected for data validation in stage 2 by real-time polymerase-chain reaction in 247 CM patients and 280 controls. ADCY3 c.675+9196T>G, CREB1 c.303+373G>A, and MITF c.938-325G>A were selected for data validation among 74 SNVs. Individuals with CREB1 GA or AA genotype and allele "A" were under 1.79 and 1.47-fold increased risks of CM than others, respectively. Excesses of CREB1 AA and MITF AA genotype were seen in patients with tumors at Clark levels III to V (27.8% versus 13.7%) and at III or IV stages (46.1% versus 24.9%) compared to others, respectively. When compared to others, patients with ADCY3 TT had 1.89 more chances of presenting CM progression, and those with MITF GA or AA had 2.20 more chances of evolving to death by CM. Our data provide, for the first time, preliminary evidence that inherited abnormalities in ADCY3, CREB1, and MITF pigmentation-related genes, not only can increase the risk to CM, but also influence CM patients' clinicopathological features.
紫外线暴露和皮肤色素沉着是皮肤黑色素瘤 (CM) 的重要宿主危险因素，众所周知，人类产生黑色素的遗传能力存在差异。本研究旨在确定与色素沉着相关的基因中的单核苷酸变异 (SNV)，这些变异与 CM 的风险和临床病理方面有关。该研究分两个阶段进行。在第一阶段，使用全基因组人类 SNV 阵列分析了 103 名 CM 患者和 103 名对照者，以确定与色素沉着相关的基因中的 SNV，然后在第二阶段通过实时聚合酶链反应在 247 名 CM 患者和 280 名对照者中选择最重要的 SNV 进行数据验证。在 74 个 SNV 中选择了 ADCY3 c.675+9196T>G、CREB1 c.303+373G>A 和 MITF c.938-325G>A 进行数据验证。与其他基因型相比，具有 CREB1 GA 或 AA 基因型和“等位基因 A”的个体患 CM 的风险分别增加了 1.79 倍和 1.47 倍。与其他基因型相比，在 Clark 水平 III 至 V（27.8%比 13.7%）和 III 或 IV 期（46.1%比 24.9%）的患者中，CREB1 AA 和 MITF AA 基因型的发生率更高。与其他患者相比，ADCY3 TT 患者 CM 进展的几率增加了 1.89 倍，而 MITF GA 或 AA 患者死于 CM 的几率增加了 2.20 倍。我们的数据首次提供了初步证据，表明 ADACY3、CREB1 和 MITF 等与色素沉着相关的基因的遗传异常不仅会增加患 CM 的风险，还会影响 CM 患者的临床病理特征。
