University of California San Francisco, Department of Dermatology, San Francisco, CA, USA; University of California San Francisco, Helen Diller Comprehensive Cancer Center, San Francisco, CA, USA.
University of California San Francisco, Department of Pathology, San Francisco, CA, USA.
Cancer Cell. 2018 Jul 9;34(1):45-55.e4. doi: 10.1016/j.ccell.2018.06.005.
We elucidated genomic and transcriptomic changes that accompany the evolution of melanoma from pre-malignant lesions by sequencing DNA and RNA from primary melanomas and their adjacent precursors, as well as matched primary tumors and regional metastases. In total, we analyzed 230 histopathologically distinct areas of melanocytic neoplasia from 82 patients. Somatic alterations sequentially induced mitogen-activated protein kinase (MAPK) pathway activation, upregulation of telomerase, modulation of the chromatin landscape, G1/S checkpoint override, ramp-up of MAPK signaling, disruption of the p53 pathway, and activation of the PI3K pathway; no mutations were specifically associated with metastatic progression, as these pathways were perturbed during the evolution of primary melanomas. UV radiation-induced point mutations steadily increased until melanoma invasion, at which point copy-number alterations also became prevalent.
我们通过对来自 82 名患者的原发性黑素瘤及其相邻前体，以及匹配的原发性肿瘤和区域转移瘤的 DNA 和 RNA 进行测序，阐明了伴随黑色素瘤从癌前病变演变而来的基因组和转录组变化。总的来说，我们分析了 230 个来自 82 名患者的具有组织病理学差异的黑素细胞肿瘤区域。体细胞改变依次诱导丝裂原活化蛋白激酶 (MAPK) 通路激活、端粒酶上调、染色质景观调节、G1/S 检查点失控、MAPK 信号上调、p53 通路失活以及 PI3K 通路激活；没有特定的突变与转移进展相关，因为这些通路在原发性黑素瘤的演变过程中受到干扰。紫外线诱导的点突变持续增加，直到黑色素瘤侵袭，此时拷贝数改变也变得普遍。
