Bianchi-Frias Daniella, Pritchard Colin, Mecham Brigham H, Coleman Ilsa M, Nelson Peter S
Division of Human Biology, Fred Hutchinson Cancer Research Center, Fairview Avenue, Seattle, WA 98109-1024, USA.
Genome Biol. 2007;8(6):R117. doi: 10.1186/gb-2007-8-6-r117.
Cancer of the prostate is influenced by both genetic predisposition and environmental factors. The identification of genes capable of modulating cancer development has the potential to unravel disease heterogeneity and aid diagnostic and prevention strategies. To this end, mouse models have been developed to isolate the influences of individual genetic lesions in the context of consistent genotypes and environmental exposures. However, the normal prostatic phenotypic variability dictated by a genetic background that is potentially capable of influencing the process of carcinogenesis has not been established.
In this study we used microarray analysis to quantify transcript levels in the prostates of five commonly studied inbred mouse strains. We applied a multiclass response t-test and determined that approximately 13% (932 genes) exhibited differential expression (range 1.3-190-fold) in any one strain relative to other strains (false discovery rate < or = 10%). Expression differences were confirmed by quantitative RT-PCR, or immunohistochemistry for several genes previously shown to influence cancer progression, such as Psca, Mmp7, and Clusterin. Analyses of human prostate transcripts orthologous to variable murine prostate genes identified differences in gene expression in benign epithelium that correlated with the differentiation state of adjacent tumors. For example, the gene encoding apolipoprotein D, which is known to enhance resistance to cell stress, was expressed at significantly greater levels in benign epithelium associated with high-grade versus low-grade cancers.
These studies support the concept that the cellular, tissue, and organismal context contribute to oncogenesis and suggest that a predisposition to a sequence of events leading to pathology may exist prior to cancer initiation.
前列腺癌受遗传易感性和环境因素的双重影响。鉴定能够调节癌症发展的基因，有可能揭示疾病的异质性，并有助于诊断和预防策略。为此，已开发出小鼠模型，以在一致的基因型和环境暴露背景下分离个体遗传损伤的影响。然而，由可能影响致癌过程的遗传背景所决定的正常前列腺表型变异性尚未得到确定。
在本研究中，我们使用微阵列分析来量化五种常用近交系小鼠前列腺中的转录水平。我们应用多类反应t检验，确定在任何一个品系中相对于其他品系约13%（932个基因）表现出差异表达（范围为1.3至190倍）（错误发现率≤10%）。通过定量RT-PCR或免疫组织化学对先前显示影响癌症进展的几个基因（如Psca、Mmp7和Clusterin）证实了表达差异。对与可变小鼠前列腺基因直系同源的人类前列腺转录本的分析，确定了良性上皮中基因表达的差异与相邻肿瘤的分化状态相关。例如已知增强细胞应激抗性的载脂蛋白D编码基因，在与高级别癌症相关的良性上皮中的表达水平明显高于低级别癌症。
这些研究支持细胞、组织和机体背景有助于肿瘤发生的概念，并表明在癌症发生之前可能存在导致病理事件序列的易感性。
