While several high-penetrance melanoma risk genes are known, variation in these genes fail to explain melanoma susceptibility in a large proportion of high-risk families. As part of a melanoma family sequencing study, including 435 families from Mediterranean populations we identified a novel NRAS variant (c.170A > C, p.D57A) in an Italian melanoma-prone family. This variant is absent in exomes in gnomAD, ESP, UKBiobank, and the 1000 Genomes Project, as well as in 11,273 Mediterranean individuals and 109 melanoma-prone families from the US and Australia. This variant occurs in the GTP-binding pocket of NRAS. Differently from other RAS activating alterations, NRAS D57A expression is unable to activate MAPK-pathway both constitutively and after stimulation but enhances EGF-induced PI3K-pathway signaling in serum starved conditions in vitro. Consistent with in vitro data demonstrating that NRAS D57A does not enrich GTP binding, molecular modeling suggests that the D57A substitution would be expected to impair Mg2 + binding and decrease nucleotide-binding and GTPase activity of NRAS. While we cannot firmly establish NRAS c.170A > C (p.D57A) as a melanoma susceptibility variant, further investigation of NRAS as a familial melanoma gene is warranted.

虽然已知一些高外显率黑色素瘤风险基因，但这些基因的变异无法解释大部分高风险家庭的黑色素瘤易感性。作为黑色素瘤家族测序研究（包括来自地中海人群的 435 个家族）的一部分，我们发现了一种新的NRAS意大利黑色素瘤易发家族中的变体（c.170A > C，p.D57A）。gnomAD、ESP、UKBiobank 和 1000 基因组计划的外显子组以及来自美国和澳大利亚的 11,273 名地中海个体和 109 个黑色素瘤易发家庭的外显子组中不存在这种变异。该变异发生在 NRAS 的 GTP 结合口袋中。与其他 RAS 激活改变不同，NRAS D57A 表达不能持续激活 MAPK 通路，也不能在刺激后激活 MAPK 通路，但在体外血清饥饿条件下增强 EGF 诱导的 PI3K 通路信号传导。与证明 NRAS D57A 不会富集 GTP 结合的体外数据一致，分子模型表明 D57A 取代预计会损害 Mg2+ 结合并降低 NRAS 的核苷酸结合和 GTP 酶活性。虽然我们不能牢固地建立NRAS c.170A > C (p.D57A) 作为黑色素瘤易感性变异，需要进一步研究NRAS作为家族性黑色素瘤基因。