Identification of cancer modifiers using parental strain expression mapping. Mus musculus

Inherited genetic risk factors play an important role in cancer. However, other than cancer susceptibility genes found in familial cancer syndromes and inherited in a Mendelian fashion, little is known about modifier genes (germline variants that interact with each other and with environmental factors) that contribute to individual susceptibility. Here we develop a strategy “parental strain expression mapping” (PSEM), which utilizes the homogeneity of inbred mice and genome-wide mRNA expression analyses, to directly identify candidate germline 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 findings in murine models, the expression of the glycolysis pathway was strongly enriched in the non-cancer prostate tissue from patients with prostate cancer who did not recur after surgical resection. Together these data suggest that PSEM can directly identify germline modifier pathways of relevance to human disease. Keywords: genetic modifier Overall design: mRNA expression profiling was carried out with 24 samples of VP from 6 inbred strains.

遗传性遗传风险因素在癌症发生过程中发挥重要作用。然而，除了在家族性癌症综合征中发现、以孟德尔方式遗传的癌症易感基因外，目前对于参与个体癌症易感性的修饰基因——即彼此间可相互作用、并可与环境因素产生联动的生殖系变异（germline variants）——的认知仍较为匮乏。
本研究开发了一种名为“亲本株系表达图谱（parental strain expression mapping, PSEM）”的分析策略，该方法借助近交系小鼠的遗传均一性与全基因组mRNA表达分析技术，可直接鉴定暴露于AKT1转基因激活条件下的不同小鼠品系间表型差异背后的候选生殖系修饰基因与调控通路。本研究共鉴定出多条候选修饰通路，其中糖酵解通路被确定为AKT1诱导细胞增殖的潜在负向修饰因子。
与小鼠模型中的研究结果相一致，在手术切除后未出现复发的前列腺癌患者的非癌性前列腺组织中，糖酵解通路的表达水平呈现显著富集状态。综上，本研究结果表明，PSEM可直接鉴定与人类疾病相关的生殖系修饰通路。
关键词：遗传修饰因子（genetic modifier）
整体实验设计：对来自6个近交品系的24个VP样本开展了mRNA表达谱分析。