Zhao S G, Jackson W C, Kothari V, Schipper M J, Erho N, Evans J R, Speers C, Hamstra D A, Niknafs Y S, Nguyen P L, Schaeffer E M, Ross A E, Den R B, Klein E A, Jenkins R B, Davicioni E, Feng F Y
Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.
1] Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Department of Biostatistics, University of Michigan Medical School, Ann Arbor, MI, USA.
Prostate Cancer Prostatic Dis. 2015 Sep;18(3):229-36. doi: 10.1038/pcan.2015.22. Epub 2015 May 19.
Although prostate cancer (PCa) is hypothesized to differ in nature between younger versus older patients, the underlying molecular distinctions are poorly understood. We hypothesized that high-throughput transcriptomic analysis would elucidate biological differences in PCas arising in younger versus older men, and would nominate potential age-specific biomarkers and therapeutic targets.
The high-density Affymetrix GeneChip platform, encompassing >1 million genomic loci, was utilized to assess gene expression in 1090 radical prostatectomy samples from patients with long-term follow-up. We identified genes associated with metastatic progression by 10 years post-treatment in younger (age<65) versus older (age⩾65) patients, and ranked these genes by their prognostic value. We performed Gene Set Enrichment Analysis (GSEA) to nominate biological concepts that demonstrated age-specific effects, and validated a target by treating with a clinically available drug in three PCa cell lines derived from younger men.
Over 80% of the top 1000 prognostic genes in younger and older men were specific to that age group. GSEA nominated the proteasome pathway as the most differentially prognostic in younger versus older patients. High expression of proteasomal genes conferred worse prognosis in younger but not older men on univariate and multivariate analysis. Bortezomib, a Food and Drug Administration approved proteasome inhibitor, decreased proliferation in three PCa cell lines derived from younger patients.
Our data show significant global differences in prognostic genes between older versus younger men. We nominate proteasomeal gene expression as an age-specific biomarker and potential therapeutic target specifically in younger men. Limitations of our study include clinical differences between cohorts, and increased comorbidities and lower survival in older patients. These intriguing findings suggest that current models of PCa biology do not adequately represent genetic heterogeneity of PCa related to age, and future clinical trials would benefit from stratification based on age.
尽管有假说认为年轻与老年前列腺癌（PCa）患者的癌症本质存在差异，但对其潜在的分子差异却知之甚少。我们推测高通量转录组分析将阐明年轻男性与老年男性前列腺癌的生物学差异，并确定潜在的年龄特异性生物标志物和治疗靶点。
利用涵盖超过100万个基因组位点的高密度Affymetrix基因芯片平台，评估1090例接受根治性前列腺切除术且有长期随访患者样本中的基因表达。我们确定了年轻（年龄<65岁）与老年（年龄⩾65岁）患者治疗后10年与转移进展相关的基因，并根据其预后价值对这些基因进行排名。我们进行了基因集富集分析（GSEA）以确定具有年龄特异性效应的生物学概念，并通过在源自年轻男性的三种前列腺癌细胞系中使用临床可用药物治疗来验证一个靶点。
年轻和老年男性中排名前1000的预后基因中，超过80%是该年龄组特有的。GSEA确定蛋白酶体途径是年轻与老年患者中预后差异最大的途径。在单变量和多变量分析中，蛋白酶体基因的高表达在年轻男性中预示着更差的预后，但在老年男性中并非如此。硼替佐米是一种经美国食品药品监督管理局批准的蛋白酶体抑制剂，可降低源自年轻患者的三种前列腺癌细胞系的增殖。
我们的数据显示老年男性与年轻男性在预后基因方面存在显著的整体差异。我们确定蛋白酶体基因表达是一种年龄特异性生物标志物，特别是在年轻男性中是潜在的治疗靶点。我们研究的局限性包括队列之间的临床差异，以及老年患者中合并症增加和生存率较低。这些有趣的发现表明，目前的前列腺癌生物学模型不能充分代表与年龄相关的前列腺癌的基因异质性，未来的临床试验将受益于基于年龄的分层。
