Melamed Rachel D, Aydin Iraz T, Rajan Geena Susan, Phelps Robert, Silvers David N, Emmett Kevin J, Brunner Georg, Rabadan Raul, Celebi Julide Tok
Department of Systems Biology and Department of Biomedical Informatics, Columbia University, New York, New York, USA; Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois, USA.
Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
J Invest Dermatol. 2017 Apr;137(4):905-909. doi: 10.1016/j.jid.2016.11.017. Epub 2016 Nov 24.
A well-defined risk factor and precursor for cutaneous melanoma is the dysplastic nevus. These benign tumors represent clonal hyperproliferation of melanocytes that are in a senescent-like state, but with occasional malignant transformation events. To portray the mutational repertoire of dysplastic nevi in patients with the dysplastic nevus syndrome and to determine the discriminatory profiles of melanocytic nevi (including dysplastic nevi) from melanoma, we sequenced exomes of melanocytic nevi including dysplastic nevi (n = 19), followed by a targeted gene panel (785 genes) characterization of melanocytic nevi (n = 46) and primary melanomas (n = 42). Exome sequencing revealed that dysplastic nevi harbored a substantially lower mutational load than melanomas (21 protein-changing mutations versus >100). Known "driver" mutations in genes for melanoma, including CDKN2A, TP53, NF1, RAC1, and PTEN, were not found among any melanocytic nevi sequenced. Additionally, melanocytic nevi including dysplastic nevi showed a significantly lower frequency and a different UV-associated mutational signature. These results show that although melanocytic nevi and dysplastic nevi harbor stable genomes with relatively few alterations, progression into melanomas requires additional mutational processes affecting key tumor suppressors. This study identifies molecular parameters that could be useful for diagnostic platforms.
发育异常痣是皮肤黑色素瘤明确的危险因素和前期病变。这些良性肿瘤代表处于衰老样状态的黑素细胞的克隆性过度增殖，但偶尔会发生恶性转化事件。为了描绘发育异常痣综合征患者中发育异常痣的突变谱，并确定黑素细胞痣（包括发育异常痣）与黑色素瘤的鉴别特征，我们对包括发育异常痣在内的黑素细胞痣（n = 19）进行了外显子组测序，随后对黑素细胞痣（n = 46）和原发性黑色素瘤（n = 42）进行了靶向基因panel（785个基因）特征分析。外显子组测序显示，发育异常痣的突变负荷明显低于黑色素瘤（21个蛋白质改变突变对>100个）。在任何测序的黑素细胞痣中均未发现黑色素瘤相关基因（包括CDKN2A、TP53、NF1、RAC1和PTEN）中的已知“驱动”突变。此外，包括发育异常痣在内的黑素细胞痣显示出明显较低的频率和不同的紫外线相关突变特征。这些结果表明，尽管黑素细胞痣和发育异常痣具有稳定的基因组，改变相对较少，但进展为黑色素瘤需要影响关键肿瘤抑制因子的额外突变过程。本研究确定了对诊断平台可能有用的分子参数。
