Identification of prostate cancer modifier pathways using parental strain expression mapping
Identification of prostate cancer modifier pathways using parental strain expression mapping
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DOI：
10.1073/pnas.0708476104
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发表时间：
2007-11-06
影响因子：
11.1
通讯作者：
Sellers, William R.
中科院分区：
文献类型：
--
作者：
Xu, Qing;Majumder, Pradip K.;Sellers, William R.
遗传风险因素在癌症中起着重要作用。然而，除了家族性癌症综合征中发现的孟德尔式癌症易感基因外，对控制个体易感性的风险修饰因子知之甚少。在这里，我们开发了一种策略，亲本株表达图谱，利用近交系小鼠的同质性和全基因组mRNA表达分析，直接识别候选生殖系修饰基因和途径暴露于转基因激活AKT1的小鼠品系之间的表型差异。我们确定了多个候选修饰剂途径，特别是糖酵解途径作为AKT1诱导增殖的候选负调节剂。与在鼠模型中的发现一致，在多个人前列腺表达数据集中，我们发现正常组织中糖酵解途径的富集与前列腺切除术后癌症复发率的降低相关。总之，这些数据表明亲本菌株表达图谱可以直接鉴定与人类疾病相关的种系修饰剂途径。
Inherited genetic risk factors play an important role in cancer. However, other than the Mendelian fashion cancer susceptibility genes found in familial cancer syndromes, little is known about risk modifiers that control individual susceptibility. Here we developed a strategy, parental strain expression mapping, that utilizes the homogeneity of inbred mice and genome-wide mRNA expression analyses to directly identify candidate germ-line modifier genes and pathways underlying phenotypic differences among murine strains exposed to transgenic activation of AKT1. We identified multiple candidate modifier pathways and, specifically, the glycolysis pathway as a candidate negative modulator of AKT1-induced proliferation. in keeping with the findings in the murine models, in multiple human prostate expression data set, we found that enrichment of glycolysis pathways in normal tissues was associated with decreased rates of cancer recurrence after prostatectomy. Together, these data suggest that parental strain expression mapping can directly identify germline modifier pathways of relevance to human disease.