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Genetic Association Analysis of Cell Cycle Regulators Reveals YWHAZ Has Prognostic Significance in Prostate Cancer.

ABSTRACT: BACKGROUND/AIM:This study aimed to identify the genes that cause biochemical recurrence (BCR) following radical prostatectomy (RP) in men with localized prostate cancer. PATIENTS AND METHODS:A two-stage genetic association study of 19 single-nucleotide polymorphisms in 11 key cell cycle regulation genes was carried out. BCR-free survival after RP was evaluated in a discovery cohort of 458 patients with prostate cancer, and replication was investigated in another cohort of 185 patients. RESULTS:A consistent association was found between BCR and rs2290291 (discovery: p=0.008; replication: p=0.029). rs2290291 is located in the tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ), and was predicted to possess a regulatory function that affected YWHAZ expression. Furthermore, YWHAZ expression was frequently up-regulated in advanced tumours, and associated with poorer survival in patients with prostate cancer. CONCLUSION:YWHAZ rs2290291 was found to be associated with BCR. YWHAZ may function as a putative oncogene during prostate cancer progression.

SUBMITTER: Yu CC

PROVIDER: S-EPMC7078838 | biostudies-literature | 2020 Mar-Apr

REPOSITORIES: biostudies-literature

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Genetic Association Analysis of Cell Cycle Regulators Reveals <i>YWHAZ</i> Has Prognostic Significance in Prostate Cancer.

Yu Chia-Cheng CC Chen Lih-Chyang LC Lin Wen-Hsin WH Lin Victor C VC Huang Chao-Yuan CY Lu Te-Ling TL Lee Cheng-Hsueh CH Huang Shu-Pin SP Bao Bo-Ying BY

Cancer genomics & proteomics 20200301 2

<h4>Background/aim</h4>This study aimed to identify the genes that cause biochemical recurrence (BCR) following radical prostatectomy (RP) in men with localized prostate cancer.<h4>Patients and methods</h4>A two-stage genetic association study of 19 single-nucleotide polymorphisms in 11 key cell cycle regulation genes was carried out. BCR-free survival after RP was evaluated in a discovery cohort of 458 patients with prostate cancer, and replication was investigated in another cohort of 185 pati ...[more]

PMID: 32108043

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Project description:Multiparameter analysis of core regulatory proteins involved in G1-S and G2-M cell-cycle transitions provides a powerful biomarker readout for assessment of the cell-cycle state. We have applied this algorithm to breast cancer to investigate how the cell cycle impacts on disease progression. Protein expression profiles of key constituents of the DNA replication licensing pathway (Mcm2, geminin) and mitotic machinery (Plk1, Aurora A and the Aurora substrate histone H3S10ph) were generated for a cohort of 182 patients and linked to clinicopathological parameters. Arrested differentiation and genomic instability were associated with an increased engagement of cells into the cell division cycle (P<0.0001). Three unique cell-cycle phenotypes were identified: (1) well-differentiated tumours composed predominantly of Mcm2-negative cells, indicative of an out-of-cycle state (18% of cases); (2) high Mcm2-expressing tumours but with low geminin, Aurora A, Plk1 and H3S10ph levels (S-G2-M progression markers), indicative of a G1-delayed/arrested state (24% cases); and (3) high Mcm2-expressing tumours and also expressing high levels of the S-G2-M progression markers, indicative of accelerated cell-cycle progression (58% of cases). The active cell-cycle progression phenotype had a higher risk of relapse when compared with out-of-cycle and G1-delayed/arrested phenotypes (HR=3.90 (1.81-8.40, P<0.001)), and was associated with Her-2 and triple negative subtypes (P<0.001). It is of note that high-grade tumours with the G1-delayed/arrested phenotype showed an identical low risk of relapse compared with well-differentiated out-of-cycle tumours (HR=1.00 (0.22-4.46), P=0.99). Our biomarker algorithm provides novel insights into the cell-cycle state of dynamic tumour cell populations in vivo. This information is of major prognostic significance and may impact on individualised therapeutic decisions. Patients with an accelerated phenotype are more likely to derive benefit from S- and M-phase-directed chemotherapeutic agents.

Dataset Information

Genetic Association Analysis of Cell Cycle Regulators Reveals YWHAZ Has Prognostic Significance in Prostate Cancer.

Publications

Genetic Association Analysis of Cell Cycle Regulators Reveals <i>YWHAZ</i> Has Prognostic Significance in Prostate Cancer.

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