Deficient mismatch repair is detected in large-to-giant congenital melanocytic naevi: providing new insight into aetiology and diagnosis
Deficient mismatch repair is detected in large-to-giant congenital melanocytic naevi: providing new insight into aetiology and diagnosis
复制标题
在大到巨大的先天性黑素细胞痣中检测到缺陷的错配修复：为病因学和诊断提供新的见解
DOI：
10.1093/bjd/ljac020
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发表时间：
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影响因子：
10.3
通讯作者：
Feng Xie
中科院分区：
文献类型：
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作者：
Boxuan Wei;Jieyu Gu;Bowen Gao;Yongyang Bao;Ran Duan;Qingfeng Li;Feng Xie
背景：大到巨的先天性黑素细胞痣（LGCMN）的病因尚不清楚。先前的一项研究发现了LGCMN患者中与缺陷错配修复（dMMR）相关的特征。然而，迄今为止，尚未对LGCMN患者的dMMR进行筛查诊断免疫组织化学（IHC）。目的探讨LGCMN的MMR状态及病因。方法对110例CMN患者进行dMMR诊断性免疫组化（MSH6、MSH2、PMS2和MLH1）筛查，其中巨CMN 30例、大CMN 30例、中CMN 30例、小CMN 20例。对照组由20名健康人的正常皮肤样本组成。对MMR体系影响不大的MMR蛋白（MSH3和PMS1）均被染色。对每位患者进行的外科手术都值得注意，因为它们可能改变CMN的行为并混淆结果。在表型数据和MMR状态之间进行二元逻辑回归分析以确定相关性。对4例患者的主痣、卫星痣和正常皮肤组织进行全外显子组测序，检测变异。进行突变特征分析以探讨LGCMN的病因。结果巨CMNs中有37%（11 / 30）、大CMNs中有23%（7 / 30）、中CMNs中有7%（2 / 30）检测到dmmr，而小CMNs和正常皮肤组织中未检测到dmmr。此外，多个LGCMNs的dMMR率远高于单个LGCMNs。回归分析显示，MMR状态与CMN大小和卫星的存在显著相关，但与年龄、性别、位置、卫星多样性和组织扩张无关。值得注意的是，LGCMN中蛋白质丢失的模式主要是PMS2的丢失。突变特征分析在LGCMN患者中检测到dmmr相关特征。此外，在LGCMN中检测到罕见的有害的DNA修复基因突变，主要是msh6、ATM、RAD50、BRCA1andERCC8。这些种系突变为单个患者的变异，意义未知。结论mmr是LGCMN的病因之一，尤其是主灶巨大和多伴灶患者。需要进一步研究DNA修复系统，特别是MMR在LGCMN中的作用。
BackgroundThe aetiologies of large-to-giant congenital melanocytic naevi (LGCMN) remain ambiguous. A previous study discovered signatures associated with deficient mismatch repair (dMMR) in patients with LGCMN. However, a screening diagnostic immunohistochemistry (IHC) panel of dMMR in patients with LGCMN has not been performed to date.ObjectivesTo identify the MMR status and aetiologies of LGCMN.MethodsA total of 110 patients with CMN, including 30 giant CMN, 30 large CMN, 30 medium CMN and 20 small CMN, underwent diagnostic IHC (for MSH6, MSH2, PMS2 and MLH1) screening of dMMR. The control group comprised normal skin samples from 20 healthy people. MMR proteins with little effect (MSH3 and PMS1) on the MMR system were stained in all samples. The surgical procedures conducted on each patient were noted because they might alter the behaviour of CMN and confound the results. Binary logistic regression analyses were performed between the phenotypic data and MMR status to identify associations. Whole-exome sequencing was performed on the main naevi, satellite naevi and normal skin tissues of four patients to detect variants. Mutational signature analyses were conducted to explore the aetiologies of LGCMN.ResultsdMMR was detected in 37% (11 of 30) of giant, 23% (7 of 30) of large and 7% (2 of 30) of medium CMNs, but were not identified in small CMNs or normal skin tissues. Moreover, multiple LGCMNs had a much higher dMMR rate than did single LGCMNs. The regression analyses showed that MMR status was significantly associated with CMN size and the presence of satellites, but was not correlated with age, sex, location, satellite diversity or tissue expansion. Notably, the pattern of protein loss in LGCMN mainly consisted of PMS2 loss. Mutational signature analyses detected dMMR-related signatures in patients with LGCMN. Additionally, rare deleterious germline mutations in DNA repair genes were detected in LGCMN, mainly inMSH6,ATM,RAD50,BRCA1andERCC8. These germline mutations were single-patient variants with unknown significance.ConclusionsdMMR is one of the aetiologies underlying LGCMN, particularly in patients with giant main lesions and multiple satellite lesions. Further studies are necessary to investigate the role of the DNA repair system, particularly MMR, in LGCMN.