Jiang Amanda, Huntsman Annabelle, Becker Carly, Feng Bing-Jian, Marks Kayla, Donigan Jessica, Duffy Keith L, Frigerio Alice, Grossman Douglas, Neklason Deborah W, Judson-Torres Robert L, Deacon Dekker C
Huntsman Cancer Institute, Salt Lake City, Utah.
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
Cancer Res Commun. 2025 Jul 1;5(7):1228-1234. doi: 10.1158/2767-9764.CRC-25-0263.
Lentigo maligna (LM) and lentigo maligna melanoma (LMM) arise from chronically sun-damaged skin. LM/LMM incidence continues to increase, particularly in Utah, where melanoma rates are twice the national average. The melanocortin-1 receptor (MC1R) has been studied in melanocyte pigmentation and DNA repair but has yet to be thoroughly investigated in LM/LMM. We investigated allele and genotype frequencies of germline MC1R variants among 175 Utah patients diagnosed with LM/LMM and 402 Utah reference individuals. The comparative analysis demonstrated an increased frequency of the D294H allele (0.046; P = 0.0042) and a decreased frequency of the V60L allele (0.074; P = 0.034) in patients with LM/LMM. The LM/LMM group demonstrated a higher OR compared with the Utah reference group associated with R151C homozygosity compared with heterozygous R151C [OR = 5.6; 95% confidence interval (CI), 0.98-32; P = 0.052] and R151C homozygosity compared with wild type (OR = 5.7; 95% CI, 1.1-30; P = 0.042). D294H heterozygosity was strongly associated with LM/LMM (OR = 3.8; 95% CI, 1.3-11; P = 0.014). Conversely, V60L heterozygosity was less strongly associated with LM/LMM (OR = 0.52; 95% CI, 0.26-1.1; P = 0.072). Stratified analyses showed no significant differences in age or gender across the key MC1R variants studied. These data highlight significant differences in MC1R allele frequencies in patients with LM/LMM, demonstrating that D294H is associated with increased LM/LMM risk, whereas the V60L variant is inversely associated with risk. This study provides the first comprehensive analysis of specific high-risk MC1R variants in patients with LM/LMM in Utah.
Our study is the first comprehensive analysis of MC1R germline variants in patients with LM/LMM in Utah, a region with an exceptionally high melanoma incidence. We draw new risk associations in LM/LMM, identifying an increased risk with the D294H and R151C variants. We also describe a novel inverse association for V60L, warranting further investigation. This study contributes to improved targeted risk stratification and an increased understanding of an understudied melanoma subtype.
恶性雀斑样痣（LM）和恶性雀斑样痣黑色素瘤（LMM）起源于长期受阳光损伤的皮肤。LM/LMM的发病率持续上升，尤其是在犹他州，该州的黑色素瘤发病率是全国平均水平的两倍。黑皮质素-1受体（MC1R）已在黑素细胞色素沉着和DNA修复方面得到研究，但在LM/LMM中尚未得到充分研究。我们调查了175名被诊断为LM/LMM的犹他州患者和402名犹他州对照个体中MC1R基因变体的等位基因和基因型频率。比较分析显示，LM/LMM患者中D294H等位基因频率增加（0.046；P = 0.0042），V60L等位基因频率降低（0.074；P = 0.034）。与犹他州对照群体相比，LM/LMM组与R151C纯合子相关的OR值更高，与杂合子R151C相比（OR = 5.6；95%置信区间[CI]，0.98 - 32；P = 0.052），与野生型相比R151C纯合子（OR = 5.7；95% CI，1.1 - 30；P = 0.042）。D294H杂合性与LM/LMM密切相关（OR = 3.8；95% CI，1.3 - 11；P = 0.014）。相反，V60L杂合性与LM/LMM的相关性较弱（OR = 0.52；95% CI，0.26 - 1.1；P = 0.072）。分层分析显示，在所研究的关键MC1R变体中，年龄或性别无显著差异。这些数据突出了LM/LMM患者中MC1R等位基因频率的显著差异，表明D294H与LM/LMM风险增加相关，而V60L变体与风险呈负相关。本研究首次对犹他州LM/LMM患者中特定的高风险MC1R变体进行了全面分析。
我们的研究首次对犹他州LM/LMM患者中的MC1R基因变体进行了全面分析，该地区黑色素瘤发病率异常高。我们在LM/LMM中发现了新的风险关联，确定D294H和R151C变体与风险增加有关。我们还描述了V60L的一种新的负相关关系，值得进一步研究。本研究有助于改进靶向风险分层，并增进对研究较少的黑色素瘤亚型的了解。
