Upregulation of shelterin and CST genes and longer telomeres are associated with unfavorable prognostic characteristics in prostate cancer

• Published in: Cancer genetics 2024-06, Vol.284-285, p.20-29
• Main Authors: dos Santos, Gabriel Arantes, Viana, Nayara I, Pimenta, Ruan, de Camargo, Juliana Alves, Guimaraes, Vanessa R, Romão, Poliana, Candido, Patrícia, dos Santos, Vinicius Genuino, Ghazarian, Vitória, Reis, Sabrina T, Leite, Katia Ramos Moreira, Srougi, Miguel
• Format: Article
• Language: English
• Subjects: Cancer Prognosis; Molecular biomarkers; Telomere-associated genes
• ISSN: 2210-7762; 2210-7770
• DOI: 10.1016/j.cancergen.2024.03.006

•Comprehensive analysis of prostate cancer samples and cell lines to explore telomeres and associated genes as prognostic biomarkers.•Despite few genetic alterations in localized disease, there is an increase in amplifications in the analyzed genes in metastatic disease.•Upregulation of shelterin and CST genes correlates with a more aggressive form of localized prostate cancer, despite limited genetic alterations.•Longer telomeres are observed in aggressive disease, indicating that increased expression of telomere-related genes could be an early biomarker for prostate cancer aggressiveness. Search for new clinical biomarkers targets in prostate cancer (PC) is urgent. Telomeres might be one of these targets. Telomeres are the extremities of linear chromosomes, essential for genome stability and control of cell divisions. Telomere homeostasis relies on the proper functioning of shelterin and CST complexes. Telomeric dysfunction and abnormal expression of its components are reported in most cancers and are associated with PC. Despite this, there are only a few studies about the expression of the main telomere complexes and their relationship with PC progression. We aimed to evaluate the role of shelterin (POT1, TRF2, TPP1, TIN2, and RAP1) and CST (CTC1, STN1, and TEN1) genes and telomere length in the progression of PC. We evaluated genetic alterations of shelterin and CST by bioinformatics in samples of localized (n = 499) and metastatic castration-resistant PC (n = 444). We also analyzed the expression of the genes using TCGA (localized PC n = 497 and control n = 152) and experimental approaches, with surgical specimens (localized PC n = 81 and BPH n = 10) and metastatic cell lines (LNCaP, DU145, PC3 and PNT2 as control) by real-time PCR. Real-time PCR also determined the telomere length in the same experimental samples. All acquired data were associated with clinical parameters. Genetic alterations are uncommon in PC, but POT1, TIN2, and TEN1 showed significantly more amplifications in the metastatic cancer. Except for CTC1 and TEN1, which are differentially expressed in localized PC samples, we did not detect an expression pattern relative to control and cell lines. Nevertheless, except for TEN1, the upregulation of all genes is associated with a worse prognosis in localized PC. We also found that increased telomere length is associated with disease aggressiveness in localized PC. The upregulation of shelterin and CST genes creates an environment that fav