Dermatology Research Centre, The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
Dermatology Research Centre, The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
J Invest Dermatol. 2018 Jul;138(7):1636-1644. doi: 10.1016/j.jid.2018.02.012. Epub 2018 Feb 22.
The melanoma transformation rate of an individual nevus is very low despite the detection of oncogenic BRAF or NRAS mutations in 100% of nevi. Acquired melanocytic nevi do, however, mimic melanoma, and approximately 30% of all melanomas arise within pre-existing nevi. Using whole-exome sequencing of 30 matched nevi, adjacent normal skin, and saliva we sought to identify the underlying genetic mechanisms for nevus development. All nevi were clinically, dermoscopically, and histopathologically documented. In addition to identifying somatic mutations, we found mutational signatures relating to UVR mirroring those found in cutaneous melanoma. In nevi we frequently observed the presence of the UVR mutation signature compared with adjacent normal skin (97% vs. 10%, respectively). Copy number aberration analysis showed that for nevi with copy number loss of tumor suppressor genes, this loss was balanced by loss of potent oncogenes. Moreover, reticular and nonspecific patterned nevi showed an increased (P < 0.0001) number of copy number aberrations compared with globular nevi. The mutation signature data generated in this study confirms that UVR strongly contributes to nevogenesis. Copy number changes reflect at a genomic level the dermoscopic differences of acquired melanocytic nevi. Finally, we propose that the balanced loss of tumor suppressor genes and oncogenes is a protective mechanism of acquired melanocytic nevi.
尽管在 100%的痣中都检测到致癌 BRAF 或 NRAS 突变，但个体痣的黑色素瘤转化率非常低。然而，获得性黑素细胞痣确实会模仿黑色素瘤，大约 30%的黑色素瘤发生在预先存在的痣内。我们通过对 30 个匹配的痣、相邻正常皮肤和唾液进行全外显子组测序，试图确定痣发育的潜在遗传机制。所有的痣都经过临床、皮肤镜和组织病理学记录。除了鉴定体细胞突变外，我们还发现了与 UVR 相关的突变特征，与皮肤黑色素瘤中发现的特征相似。与相邻正常皮肤相比（分别为 97%和 10%），我们在痣中经常观察到 UVR 突变特征的存在。拷贝数异常分析表明，对于具有肿瘤抑制基因拷贝数缺失的痣，这种缺失通过失去潜在的致癌基因得到平衡。此外，网状和非特异性图案性痣与球形痣相比，显示出更多的拷贝数异常（P<0.0001）。本研究产生的突变特征数据证实，UVR 强烈促进痣发生。拷贝数变化反映了获得性黑素细胞痣的皮肤镜差异在基因组水平上的变化。最后，我们提出，肿瘤抑制基因和致癌基因的平衡丢失是获得性黑素细胞痣的一种保护机制。
