Department of Surgery Oncology and Gastroenterology, University of Padova, Padova, Italy.
First Surgical Clinic, Azienda Ospedaliera Padova, Padova, Italy.
J Transl Med. 2021 Feb 6;19(1):57. doi: 10.1186/s12967-021-02725-5.
Melanoma is the deadliest of skin cancers and has an increasing annual incidence worldwide. It is a multi-factorial disease most likely arising from both genetic predisposition and environmental exposure to ultraviolet light. Genetic variability of the components of the biological circadian clock is recognized to be a risk factor for different type of cancers. Moreover, two variants of a clock gene, RORA, have been associated with melanoma patient's prognosis. Our aim is to test the hypothesis that specific single nucleotide polymorphisms (SNPs) of the circadian clock genes may significantly influence the predisposition to develop cutaneous melanoma or the outcome of melanoma patients.
We genotyped 1239 subjects, 629 cases of melanoma and 610 healthy controls in 14 known SNPs of seven selected clock genes: AANAT, CLOCK, NPAS2, PER1, PER2, RORA, and TIMELESS. Genotyping was conducted by q-PCR. Multivariate logistic regression was employed for susceptibility of melanoma assessment, modeled additively. Subgroup analysis was performed by gender. For the female subgroup, a further discrimination was performed by age. For prognosis of melanoma assessment, multivariate Cox proportional hazard regression was employed. The Benjamini-Hochberg method was utilized as adjustment for multiple comparisons.
We identified two RORA SNPs statistically significant with respect to the association with melanoma susceptibility. Considering the putative role of RORA as a nuclear steroid hormone receptor, we conducted a subgroup analysis by gender. Interestingly, the RORA rs339972 C allele was associated with a decreased predisposition to develop melanoma only in the female subgroup (OR 0.67; 95% CI 0.51-0.88; P = 0.003) while RORA rs10519097 T allele was associated with a decreased predisposition to develop melanoma only in the male subgroup (OR 0.62; 95% CI 0.44-0.87; P = 0.005). Moreover, the RORA rs339972 C allele had a decreased susceptibility to develop melanoma only in females aged over 50 years old (OR 0.67; 95% CI 0.54-0.83; P = 0.0002). None of the studied SNPs were significantly associated with the prognosis.
Overall, we cannot ascertain that circadian pathway genetic variation is involved in melanoma susceptibility or prognosis. Nevertheless, we identified an interesting relationship between melanoma susceptibility and RORA polymorphisms acting in sex-specific manner and which is worth further future investigation.
黑色素瘤是皮肤癌中最致命的一种，其全球发病率呈逐年上升趋势。它是一种多因素疾病，很可能是遗传易感性和暴露于紫外线的环境因素共同作用的结果。生物昼夜节律钟成分的遗传变异性被认为是多种癌症的风险因素。此外，时钟基因 RORA 的两个变体与黑色素瘤患者的预后相关。我们的目的是检验以下假设，即昼夜节律钟基因的特定单核苷酸多态性（SNP）可能显著影响发展皮肤黑色素瘤的易感性或黑色素瘤患者的预后。
我们对 1239 名受试者进行了基因分型，其中 629 名黑色素瘤患者和 610 名健康对照者，涉及七个选定的时钟基因中的 14 个已知 SNP：AANAT、CLOCK、NPAS2、PER1、PER2、RORA 和 TIMELESS。基因分型采用 q-PCR 进行。采用多元逻辑回归对黑色素瘤易感性进行模型加性评估。根据性别进行亚组分析。对于女性亚组，进一步按年龄进行区分。对于黑色素瘤预后评估，采用多元 Cox 比例风险回归。采用 Benjamini-Hochberg 方法进行多重比较调整。
我们发现两个 RORA SNP 与黑色素瘤易感性显著相关。考虑到 RORA 作为核甾体激素受体的假定作用，我们根据性别进行了亚组分析。有趣的是，RORA rs339972 C 等位基因仅与女性亚组中黑色素瘤发病风险降低相关（OR 0.67；95%CI 0.51-0.88；P=0.003），而 RORA rs10519097 T 等位基因仅与男性亚组中黑色素瘤发病风险降低相关（OR 0.62；95%CI 0.44-0.87；P=0.005）。此外，RORA rs339972 C 等位基因仅在 50 岁以上的女性中降低了黑色素瘤发病的易感性（OR 0.67；95%CI 0.54-0.83；P=0.0002）。研究的 SNP 均与预后无显著相关性。
总体而言，我们不能确定昼夜节律途径的遗传变异是否参与了黑色素瘤的易感性或预后。然而，我们发现了一个有趣的关系，即 RORA 多态性与黑色素瘤易感性有关，这种关系以性别特异性的方式发挥作用，值得进一步的未来研究。
