The cyclic AMP pathway is a sex-specific modifier of glioma risk in type I neurofibromatosis patients.
The cyclic AMP pathway is a sex-specific modifier of glioma risk in type I neurofibromatosis patients.
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DOI：
10.1158/0008-5472.can-14-1891
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发表时间：
2015-01-01
期刊：
影响因子：
11.2
通讯作者：
Rubin JB
中科院分区：
文献类型：
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作者：
Warrington NM;Sun T;Luo J;McKinstry RC;Parkin PC;Ganzhorn S;Spoljaric D;Albers AC;Merkelson A;Stewart DR;Stevenson DA;Viskochil D;Druley TE;Forys JT;Reilly KM;Fisher MJ;Tabori U;Allen JC;Schiffman JD;Gutmann DH;Rubin JB
确定1型神经纤维瘤病（NF1）患者中胶质瘤风险的调节因子有助于支持个性化的肿瘤监测，增进对胶质瘤发生的理解，并有可能确定新的治疗靶点。在此我们报道了人腺苷酸环化酶基因ADCY8中的基因多态性，其以性别特异性的方式与NF1中的胶质瘤风险相关，增加女性的风险，同时降低男性的风险。这一发现扩展了基于基因工程小鼠模型（Nf1 GEM）结果的环磷腺苷（cAMP）在胶质瘤发生中作用的早期证据。因此，性别二态性的cAMP信号传导可能使男性和女性对cAMP水平的变化具有不同的敏感性。利用雄性和雌性Nf1 GEM，我们发现cAMP调节以及cAMP抑制的生长促进作用存在显著的性别差异。总体而言，我们的研究结果确立了cAMP调节在人类胶质瘤发生中的性别特异性作用，特别确定了ADCY8是NF1中胶质瘤风险的调节因子。
Identifying modifiers of glioma risk in patients with type 1 neurofibromatosis (NF1) could help support personalized tumor surveillance, advance understanding of gliomagenesis and potentially identify novel therapeutic targets. Here we report genetic polymorphisms in the human adenylate cyclase gene ADCY8 which correlate with glioma risk in NF1 in a sex-specific manner, elevating risk in females while reducing risk in males. This finding extends earlier evidence of a role for cAMP in gliomagenesis based on results in a genetically engineered mouse model (Nf1 GEM). Thus, sexually dimorphic cAMP signaling might render males and females differentially sensitive to variation in cAMP levels. Using male and female Nf1 GEM, we found significant sex differences exist in cAMP regulation and in the growth promoting effects of cAMP suppression. Overall, our results establish a sex-specific role for cAMP regulation in human gliomagenesis, specifically identifying ADCY8 as a modifier of glioma risk in NF1.