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

前列腺基质基因表达的综合表征及其与致死性前列腺癌的关联

• 批准号: 10759608
• 负责人: KATHRYN L PENNEY
• 金额: $ 45.39万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10759608
• 关键词: Address; Affect; Area; Attention; Behavior; Bioinformatics; Biological Markers; Biology; Biopsy Specimen; Cancer Biology; Cancer Etiology; Cancer Patient; Cellular biology; Cessation of life; DNA Sequence Alteration; Data; Development; Diagnosis; Disease; Disease Progression; Endothelial Cells; Epithelium; Fibroblasts; Fluorescence; Follow-Up Studies; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genetic Risk; Genetic Transcription; Gleason Grade for Prostate Cancer; Health; Health Professional; Immune; Immunohistochemistry; Indolent; Inflammation; Inherited; Lasers; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Molecular; Morphology; Mutation; Neoplasm Metastasis; Outcome; Pathologic; Pathway interactions; Patients; Pattern; Physicians; Pilot Projects; Play; Prognosis; Prognostic Marker; Proliferating; Property; Prostate; Prostatic Neoplasms; Quantitative Trait Loci; Radical Prostatectomy; Research; Research Personnel; Risk; Role; Signal Transduction; Smooth Muscle; Specimen; Stains; Stromal Cells; Testing; Tissue Microarray; Tissue Stains; Tissues; Tumor Biology; Tumor Promotion; Work; biomarker development; cancer diagnosis; cancer subtypes; cancer survival; cell motility; cell stroma; cell type; clinical care; cohort; differential expression; genetic variant; genome-wide; genomic predictors; improved; innovation; men; molecular marker; molecular subtypes; overtreatment; predictive signature; prognostic; prognostic assays; programs; prostate biopsy; prostate cancer cell; prostate cancer risk; risk variant; synergism; targeted treatment; tumor; tumor initiation; tumor microenvironment; tumor progression

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.

摘要 前列腺癌的预后具有异质性，临床医生和研究人员仍然缺乏确定的手段， 区分潜在致命性疾病和惰性疾病。发现分子生物标志物， 在诊断时鉴别惰性前列腺癌与潜在致死性前列腺癌将增强 确定哪些患者会从立即治疗中受益更多，哪些患者会得到更好的服务， 主动监视基因表达与致死性前列腺癌相关性的研究， 主要集中在肿瘤上皮细胞;然而，前列腺微环境已经吸引了越来越多的 注意力是癌症进展的关键驱动力。来自微环境的信号因素影响 上皮获得特性，如增加的运动性、增殖和侵入行为。尽管有这些 重要的发现，基质基因表达的表征仅在小规模上得到解决。我们 先前使用来自前列腺癌细胞的表达数据鉴定的与前列腺癌侵袭性相关的基因， 25例根治性前列腺切除术标本的激光捕获显微切割基质。此外，我们还展示了 前列腺癌中的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，几种遗传性前列腺癌风险变异的功能是 在肿瘤和正常上皮中表达数量性状基因座;然而，并非所有风险SNP都与肿瘤和正常上皮中的表达相关。 这可能是因为遗传变异的影响是组织特异性的。我们现在扩展这些 分析集中于前列腺基质的基因表达。我们假设（1）基因表达特征 在间质中（单独或与上皮基因表达标记组合）是前列腺癌的预测因子 侵袭性和结果;（2）具有不同DNA改变的前列腺癌亚型与 （3）前列腺癌风险变体与基质基因表达相关;和 (4)肿瘤周围基质中细胞类型的组成可以预测前列腺癌 侵略性和结果。为了验证这些假设，我们将进行肿瘤的基因表达谱分析- 400例前列腺癌病例（包括115例致死性病例）， 来自医师健康研究和健康专业人员随访的上皮基因表达数据 研究肿瘤队列。我们还将对组织微阵列进行多重免疫组织化学染色 包括1500例前列腺癌病例（117例致死病例），以研究基质细胞类型组成。在我们 项目，我们创新性地将联合收割机遗传学、肿瘤和微环境生物学以及生物标志物开发相结合， 使用严格的统计和生物信息学方法。关注邻近的间质组织 通过显著增加可用的上皮分子预后测试，为临床护理带来变革。一个 对微环境在肿瘤发生和发展中的作用的进一步理解也可能 可能导致基质靶向治疗的发展。