High-Throughput Transcriptomic Analysis Nominates Proteasomal Genes As Age Specific Biomarkers and Therapeutic Targets in Prostate Cancer

Abstract

BACKGROUND: 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. METHODS: The high-density Affymetrix GeneChip platform, encompassing 41 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 (ageo65) 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 agespecific effects, and validated a target by treating with a clinically available drug in three PCa cell lines derived from younger men. RESULTS: 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. CONCLUSIONS: 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.

Prostate cancer aggressiveness and age: Impact of p53, BCL-2 and microvessel density

“…We found evidence of biologically more aggressive disease in men ≥80 years old than in men younger than 70 years, based on a) evidence consistent with previously reported associations of age and Gleason score,22 and b) novel results showing twofold and statistically significant increases in odds of positive p53 staining and higher MVD, after adjusting for race, screening status, PSA level, and Gleason score. The strength of association for bcl-2 staining was similar for men aged 80 years and older, but the result was not statistically significant in adjusted analyses.…”

“…Recent studies have found dysregulated genes associated with DNA repair and androgen signaling in men over age 70 years,23 and also substantial differences in genes associated with progression to metastatic disease between older and younger groups 22. In addition, although published results are not entirely consistent, investigators are finding age differences for molecular markers in other tumor sites, including overexpression of TP53 in older (versus younger) individuals in meningioma, gastric cancer, and endometrial cancers 24–26.…”

Prostate cancer in young men represents a distinct clinical phenotype: gene expression signature to predict early metastases

“…However, no prognostic signature was tailored to predict aggressive CaP in men younger than age 55 years. Converging data from clinical and molecular genetic studies provide strong evidence that CaP in young men represents a distinct clinical phenotype with underlying biological differences compared to older men [9][10][11][12][13] . We hypothesized that age-related differences in tumor biology have implications for prognosis of early-onset CaPs.…”