Precision Medicine Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Department of Dermatology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
J Invest Dermatol. 2023 Jul;143(7):1187-1196.e9. doi: 10.1016/j.jid.2023.01.006. Epub 2023 Jan 28.
Normal skin contains numerous clones carrying cancer driver mutations. However, the mutational landscape of normal skin and its clonal relationship with skin cancer requires further elucidation. The aim of our study was to investigate the mutational landscape of normal human skin. We performed whole-exome sequencing using physiologically normal skin tissues and the matched peripheral blood (n = 39) and adjacent-matched skin cancers from a subset of patients (n = 10). Exposed skin harbored a median of 530 mutations (10.4/mb, range = 51-2,947), whereas nonexposed skin majorly exhibited significantly fewer mutations (median = 13, 0.25/mb, range = 1-166). Patient age was significantly correlated with the mutational burden. Mutations in six driver genes (NOTCH1, FAT1, TP53, PPM1D, KMT2D, and ASXL1) were identified. De novo mutational signature analysis identified a single signature with components of UV- and aging-related signatures. Normal skin harbored only three instances of copy-neutral loss of heterozygosity in 9q (n = 2) and 6q (n = 1). The mutational burden of normal skin was not correlated with that of matched skin cancers, and no protein-coding mutations were shared. In conclusion, we revealed the mutational landscape of normal skin, highlighting the role of driver genes in the malignant progression of normal skin.
正常皮肤中含有大量携带癌症驱动突变的克隆。然而，正常皮肤的突变景观及其与皮肤癌的克隆关系仍需进一步阐明。我们的研究旨在调查正常人类皮肤的突变景观。我们使用生理正常的皮肤组织和来自部分患者的匹配外周血（n=39）和相邻匹配皮肤癌（n=10）进行了全外显子组测序。暴露皮肤携带的突变中位数为 530 个（10.4/mb，范围 51-2947），而非暴露皮肤主要表现出明显较少的突变（中位数为 13 个，0.25/mb，范围 1-166）。患者年龄与突变负担显著相关。鉴定了六个驱动基因（NOTCH1、FAT1、TP53、PPM1D、KMT2D 和 ASXL1）中的突变。从头突变特征分析确定了一个具有 UV 和与年龄相关特征成分的单一特征。正常皮肤在 9q（n=2）和 6q（n=1）中仅出现三个拷贝中性杂合性丢失的实例。正常皮肤的突变负担与匹配皮肤癌的突变负担不相关，也没有共享的蛋白质编码突变。总之，我们揭示了正常皮肤的突变景观，强调了驱动基因在正常皮肤恶性进展中的作用。
