Comprehensive characterization of prostate stromal gene expression and association with lethal prostate cancer

摘要 前列腺癌的预后是不同的，临床医生和研究人员仍然缺乏明确的方法来治疗 区分潜在的致命疾病和惰性疾病。分子生物标记物的发现 在诊断时识别惰性前列腺癌和潜在致命性前列腺癌将增强 确定哪些患者将从立即治疗中受益更多，哪些患者得到更好的服务 主动监视。关于基因表达与致死性前列腺癌的关系的研究已经 主要集中在肿瘤上皮；然而，前列腺微环境已经吸引了越来越多的人 注意力是癌症进展的关键驱动因素。来自微环境的信号因素影响 上皮细胞获得的特性，如运动性增强、增殖和侵袭性行为。尽管如此 尽管有重要的发现，但对间质基因表达的表征仅在小范围内得到了解决。我们 使用来自PURSE的表达数据，先前发现了与前列腺癌侵袭性相关的基因 激光显微切割25例前列腺癌根治术标本的间质。此外，我们还展示了 前列腺癌的DNA改变与上皮组织中独特的转录程序有关。 我们和其他人已经确定了几种遗传性前列腺癌风险变异的功能 数量性状基因座在肿瘤和正常上皮中的表达；然而，并不是所有的风险SNPs都是相关的 基因表达，可能是因为基因变异的影响是组织特有的。我们现在延长这些 重点分析前列腺间质的基因表达。我们假设(1)一个基因表达特征 间质中(单独或结合上皮基因表达特征)是前列腺癌的预测因素 侵袭性和预后；(2)具有不同DNA改变的前列腺癌亚型与 间质中的基因表达；(3)前列腺癌风险变异与间质中的基因表达有关；以及 (4)肿瘤周围间质中细胞类型的组成可能预示着前列腺癌。 进攻性和结果。为了验证这些假设，我们将对肿瘤进行基因表达谱分析- 和正常相关间质用于约400例前列腺癌病例(包括115例死亡病例) 来自医生健康研究和卫生专业人员随访的上皮基因表达数据 研究肿瘤队列。我们还将对组织芯片进行多重免疫组织化学染色 由1500例前列腺癌病例(117例致死病例)组成，研究间质细胞类型组成。在我们的 项目，我们创新性地将遗传学、肿瘤和微环境生物学以及生物标记物的开发结合在一起 使用严格的统计和生物信息学方法。对邻近间质组织的关注可能是 通过显著增加可用的上皮分子预后测试，为临床护理带来了变革。一个 更好地理解微环境在肿瘤发生和发展中的作用也可能 这可能会导致基质靶向疗法的发展。

Abstract Prostate cancer has a heterogeneous prognosis, and clinicians and researchers still lack definitive means to distinguish potentially lethal from indolent disease. Discovery of molecular biomarkers that improve the identification of indolent versus potentially lethal prostate cancer at diagnosis would enhance the ability to determine which patients would benefit more from immediate treatment and those who are better served by active surveillance. Studies of the association of gene expression with lethal prostate cancer have predominantly focused on the tumor epithelium; however, the prostate microenvironment has drawn increasing attention as a critical driver of cancer progression. Signaling factors from the microenvironment influence the epithelium to acquire properties such as increased motility, proliferation, and invasive behavior. Despite these important findings, characterization of stromal gene expression has been addressed only on a small scale. We previously identified genes associated with prostate cancer aggressiveness using expression data from pure laser-capture microdissected stroma from 25 radical prostatectomy specimens. We additionally have shown that DNA alterations in prostate cancer are associated with unique transcriptional programs in epithelial tissue. We and others have determined that several of the inherited prostate cancer risk variants function as expression Quantitative Trait Loci in tumor and normal epithelium; however, not all risk SNPs were associated with gene expression, possibly because the impact of genetic variants is tissue specific. We now extend these analyses to focus on gene expression of prostate stroma. We hypothesize that (1) a gene expression signature in stroma (alone or in combination with an epithelial gene expression signature) is predictive of prostate cancer aggressiveness and outcome; (2) prostate cancer subtypes with distinct DNA alterations are associated with gene expression in stroma; (3) prostate cancer risk variants are associated with stromal gene expression; and (4) the composition of cell types within the stroma surrounding the tumor may be predictive of prostate cancer aggressiveness and outcome. To test these hypotheses, we will perform gene expression profiling of tumor- and normal- associated stroma for ~400 prostate cancer cases (including 115 lethal cases) with existing epithelial gene expression data from the Physicians’ Health Study and the Health Professionals Follow-up Study Tumor Cohort. We will also perform multiplex immunohistochemical staining of tissue microarrays consisting of 1500 prostate cancer cases (117 lethal cases) to study stroma cell type composition. In our project, we innovatively combine genetics, tumor and microenvironment biology, and biomarker development using rigorous statistical and bioinformatics approaches. Focus on adjacent stromal tissue is potentially transformative for clinical care by significantly adding to available epithelial molecular prognostic tests. An improved understanding of the role of the microenvironment in tumor initiation and progression may also potentially lead to the development of stroma-targeted therapies.