Frazer Institute, University of Queensland, Dermatology Research Centre, Brisbane, Australia.
QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland, Australia.
Br J Dermatol. 2023 May 24;188(6):770-776. doi: 10.1093/bjd/ljad041.
Population-wide screening for melanoma is not cost-effective, but genetic characterization could facilitate risk stratification and targeted screening. Common Melanocortin-1 receptor (MC1R) red hair colour (RHC) variants and Microphthalmia-associated transcription factor (MITF) E318K separately confer moderate melanoma susceptibility, but their interactive effects are relatively unexplored.
To evaluate whether MC1R genotypes differentially affect melanoma risk in MITF E318K+ vs. E318K- individuals.
Melanoma status (affected or unaffected) and genotype data (MC1R and MITF E318K) were collated from research cohorts (five Australian and two European). In addition, RHC genotypes from E318K+ individuals with and without melanoma were extracted from databases (The Cancer Genome Atlas and Medical Genome Research Bank, respectively). χ2 and logistic regression were used to evaluate RHC allele and genotype frequencies within E318K+/- cohorts depending on melanoma status. Replication analysis was conducted on 200 000 general-population exomes (UK Biobank).
The cohort comprised 1165 MITF E318K- and 322 E318K+ individuals. In E318K- cases MC1R R and r alleles increased melanoma risk relative to wild type (wt), P < 0.001 for both. Similarly, each MC1R RHC genotype (R/R, R/r, R/wt, r/r and r/wt) increased melanoma risk relative to wt/wt (P < 0.001 for all). In E318K+ cases, R alleles increased melanoma risk relative to the wt allele [odds ratio (OR) 2.04 (95% confidence interval 1.67-2.49); P = 0.01], while the r allele risk was comparable with the wt allele [OR 0.78 (0.54-1.14) vs. 1.00, respectively]. E318K+ cases with the r/r genotype had a lower but not significant melanoma risk relative to wt/wt [OR 0.52 (0.20-1.38)]. Within the E318K+ cohort, R genotypes (R/R, R/r and R/wt) conferred a significantly higher risk compared with non-R genotypes (r/r, r/wt and wt/wt) (P < 0.001). UK Biobank data supported our findings that r did not increase melanoma risk in E318K+ individuals.
RHC alleles/genotypes modify melanoma risk differently in MITF E318K- and E318K+ individuals. Specifically, although all RHC alleles increase risk relative to wt in E318K- individuals, only MC1R R increases melanoma risk in E318K+ individuals. Importantly, in the E318K+ cohort the MC1R r allele risk is comparable with wt. These findings could inform counselling and management for MITF E318K+ individuals.
人群黑色素瘤筛查并不具有成本效益，但遗传特征分析可以帮助进行风险分层和靶向筛查。常见的黑素皮质素 1 受体（MC1R）红发颜色（RHC）变体和小眼畸形相关转录因子（MITF）E318K 分别赋予中等水平的黑色素瘤易感性，但它们的相互作用相对较少被研究。
评估 MC1R 基因型是否会影响 MITF E318K+与 E318K-个体的黑色素瘤风险。
从研究队列（五个澳大利亚和两个欧洲）中收集黑色素瘤状态（患病或未患病）和基因型数据（MC1R 和 MITF E318K）。此外，从分别为 E318K+个体黑色素瘤数据库（癌症基因组图谱和医学基因组研究银行）中提取 E318K+个体的 RHC 基因型。利用卡方检验和逻辑回归评估 E318K+/-队列中根据黑色素瘤状态的 RHC 等位基因和基因型频率。在 20 万例一般人群外显子组（英国生物银行）中进行了复制分析。
该队列包括 1165 名 MITF E318K-和 322 名 E318K+个体。在 E318K-病例中，与野生型（wt）相比，MC1R R 和 r 等位基因增加了黑色素瘤风险，P<0.001。同样，与 wt/wt 相比，每种 MC1R RHC 基因型（R/R、R/r、R/wt、r/r 和 r/wt）均增加了黑色素瘤风险（P<0.001）。在 E318K+病例中，R 等位基因增加了黑色素瘤风险，而 r 等位基因的风险与 wt 等位基因相似[比值比（OR）2.04（95%置信区间 1.67-2.49）；P=0.01]。E318K+病例中 r/r 基因型的黑色素瘤风险相对 wt/wt 较低，但无统计学意义[OR 0.52（0.20-1.38）]。在 E318K+队列中，与非 R 基因型（r/r、r/wt 和 wt/wt）相比，R 基因型（R/R、R/r 和 R/wt）显著增加了黑色素瘤风险（P<0.001）。英国生物银行的数据支持了我们的发现，即 r 不会增加 E318K+个体的黑色素瘤风险。
在 MITF E318K-和 E318K+个体中，RHC 等位基因/基因型以不同方式改变黑色素瘤风险。具体而言，尽管所有 RHC 等位基因均增加了 E318K-个体的风险，但仅 MC1R R 增加了 E318K+个体的黑色素瘤风险。重要的是，在 E318K+队列中，MC1R r 等位基因的风险与 wt 相似。这些发现可为 MITF E318K+个体的咨询和管理提供信息。
