Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.
Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
Pathology. 2022 Aug;54(5):533-540. doi: 10.1016/j.pathol.2021.12.289. Epub 2022 Mar 2.
Evolution from a benign naevus to a melanoma results principally from the stepwise accumulation of mutations. We used a custom next generation sequencing (NGS) panel targeting specific melanoma associated genes to analyse and compare differences between melanomas and their precursor naevi in coding and non-coding mutations and copy number aberrations, with a view to implementing this technique as an ancillary test to assist in the interpretation of difficult to diagnose melanocytic tumours. Fifteen cases of cutaneous melanoma with an adjacent morphologically benign (presumed precursor) naevus were selected. A custom NGS panel was used to sequence 54 melanoma associated genes in both the melanoma and the associated naevus for each case. In three cases, two morphologically distinct regions of the melanoma were sequenced. The adjacent (non-lesional) skin was also tested in nine cases. One case was excluded following molecular testing and clinicopathological reclassification as an epidermotropic melanoma metastasis. Twelve of the 14 tumours showed either BRAF or NRAS driver mutations. The melanomas harboured significantly more mutations than the adjacent naevi, particularly in non-coding promoter regions (p=0.002). There were significantly more non-coding promotor mutations in NRAS-mutant melanomas than BRAF-mutant melanomas (p=0.004). Mutations in TERT promoter regions were found preferentially in melanomas. Oncogenic events found exclusively in melanomas included PTEN loss in two BRAF-mutant melanomas and RAC1 P29S hyperactivating mutations in two NRAS-mutant melanomas. Higher numbers of mutations were present in melanomas compared to their precursor naevi. These findings support the further evaluation of this melanoma custom NGS panel as an ancillary test for interpreting difficult borderline melanocytic lesions.
从良性痣发展为黑色素瘤主要是由于突变的逐步积累。我们使用了一个针对特定黑色素瘤相关基因的定制下一代测序 (NGS) 面板，来分析和比较黑色素瘤与其前体痣之间在编码和非编码突变以及拷贝数异常方面的差异，以期将这项技术作为辅助测试来协助解释难以诊断的黑色素瘤肿瘤。选择了 15 例具有形态良性（假定为前体）痣的皮肤黑色素瘤。为每个病例使用定制的 NGS 面板对黑色素瘤和相关痣中的 54 个黑色素瘤相关基因进行测序。在三个病例中，对黑色素瘤的两个形态不同的区域进行了测序。在九个病例中还对相邻（非病变）皮肤进行了测试。在分子检测和临床病理重新分类为表皮浸润性黑色素瘤转移后，一个病例被排除在外。14 个肿瘤中有 12 个显示 BRAF 或 NRAS 驱动突变。黑色素瘤比相邻的痣具有更多的突变，尤其是在非编码启动子区域（p=0.002）。NRAS 突变黑色素瘤中非编码启动子突变明显多于 BRAF 突变黑色素瘤（p=0.004）。TERT 启动子区域的突变优先发生在黑色素瘤中。仅在黑色素瘤中发现的致癌事件包括两个 BRAF 突变黑色素瘤中 PTEN 缺失和两个 NRAS 突变黑色素瘤中 RAC1 P29S 激活突变。与前体痣相比，黑色素瘤中存在更多的突变。这些发现支持进一步评估这种黑色素瘤定制 NGS 面板作为辅助测试来解释边界难辨的黑色素瘤病变。
