Recent pan-cancer genomic analyses have identified numerous oncogenic driver mutations that occur in a cell-type and tissue-specific distribution. For example, oncogenic mutations in Braf and Nras genes arise predominantly in melanocytic neoplasms of the epidermis, while oncogenic mutations in Gnaq/11 genes arise mostly in melanocytic lesions of the dermis or the uvea. The mechanisms promoting cell-type and tissue-specific oncogenic events currently remain poorly understood. Here, we report that Gnaq/11 hotspot mutations occur as early oncogenic drivers during the evolution of primary melanomas in Hgf-Cdk4 mice. Additional single base substitutions in the Trp53 gene and structural chromosomal aberrations favoring amplifications of the chromosomal region containing the Met receptor gene accumulate during serial tumor transplantation and in cell lines established in vitro. Mechanistically, we found that the Gnaq^Q209L mutation transactivates the Met receptor. Overexpression of oncogenic Gnaq^Q209L in the immortalized melanocyte cell line promoted in vivo growth that was enhanced by transgenic Hgf expression in the tumor microenvironment. This cross-signaling mechanism explains the selection of oncogenic Gnaq/11 in primary Hgf-Cdk4 melanomas and provides an example of how oncogenic driver mutations, intracellular signaling cascades, and microenvironmental cues cooperate to drive cancer development in a tissue-specific fashion.

最近的泛癌基因组分析发现了许多发生在细胞类型和组织特异性分布中的致癌驱动突变。例如，Braf和Nras基因的致癌突变主要出现在表皮的黑素细胞肿瘤中，而Gnaq/11基因的致癌突变主要出现在真皮或葡萄膜的黑素细胞病变中。目前对促进细胞类型和组织特异性致癌事件的机制仍知之甚少。在这里，我们报告Gnaq/11热点突变作为 Hgf-Cdk4 小鼠原发性黑色素瘤进化过程中的早期致癌驱动因素发生。Trp53基因中额外的单碱基取代和有利于含有 Met 受体基因的染色体区域扩增的染色体结构畸变在连续肿瘤移植期间和体外建立的细胞系中积累。从机制上讲，我们发现 Gnaq ^Q209L突变会反式激活 Met 受体。永生化黑素细胞系中致癌 Gnaq ^Q209L的过度表达促进体内生长，肿瘤微环境中的转基因 Hgf 表达可增强这种生长。这种交叉信号传导机制解释了原发性 Hgf-Cdk4 黑色素瘤中致癌Gnaq/11的选择，并提供了致癌驱动突变、细胞内信号级联和微环境线索如何协作以组织特异性方式驱动癌症发展的示例。