A 10‑gene signature as a predictor of biochemical recurrence after radical prostatectomy in patients with prostate cancer and a Gleason score ≥7

Abstract

The time and speed of biochemical recurrence (BCR) of prostate cancer (PCa) after radical prostatectomy (RP) is highly variable. Stratification methods based on TNM staging and Gleason score (GS) do not allow the identification of patients at risk of BCR following RP. Therefore, the aim of the present study was to identify molecular signatures that can predict BCR risk effectively and facilitate treatment-related decisions for patients with PCa. RNA sequencing data and corresponding clinical data were downloaded from The Cancer Genome Atlas (TCGA) and Oncomine databases. Bioinformatics analysis was performed to identify differentially expressed genes in patients with GS=6 and GS ≥7. Cox regression models were used to determine the PCa signature (PCasig) and a clinical nomogram for the prediction of BCR. The performance of nomograms was assessed using time-dependent receiver operating characteristic curves and the concordance index (C-index). A PCasig comprising 10 genes, including SEMG2, KCNJ16, TFAP2B, SYCE1, KCNU1, AFP, GUCY1B2, GRIA4, NXPH1 and SOX11, was significantly associated with BCR, which was identified in TCGA cohort [hazard ratio (HR), 5.18; 95% CI, 3.241–8.272; C-index, 0.777] and validated in the Oncomine cohort (HR, 2.78; 95% CI, 1.39–5.54; C-index, 0.66). The expression levels of SEMG2, KCNJ16 and TFAP2B were downregulated in patients with GS ≥7. The expression levels of SYCE1, KCNU1, AFP, GUCY1B2, GRIA4, NXPH1 and SOX11 were upregulated in patients with GS ≥7. The clinical nomogram was constructed based on the GS and pathologic T stage (HR, 4.15; 95% CI, 1.39–5.54; C-index, 0.713). The addition of the PCasig to the clinical nomogram significantly improved prognostic value (HR, 7.25; 95% CI, 4.54–11.56; C-index, 0.782) with an net reclassification improvement of 75.3% (95% CI, 46.8–104.6%). Furthermore, the endogenous expression of each gene in the PCasig was measured in five PCa cell lines and in normal prostate cells, and these genes exhibited different expression levels relative to one another. In conclusion, an PCasig was identified by mining TCGA and successfully validated in an Oncomine cohort. This PCasig was an independent prognostic factor with a greater prognostic value for all patients regardless of GS than traditional clinical variables, which can improve the performance of clinical nomograms in predicting BCR of patients with GS ≥7.

Identification of a Five-Gene Signature Derived From MYCN Amplification and Establishment of a Nomogram for Predicting the Prognosis of Neuroblastoma

“…In a study of intraductal papillary mucinous neoplasms (IPMNs), NXPH1 was more likely to be methylated in low-grade dysplasia than in high-grade dysplasia ( Hong et al, 2012 ). NXPH1 was incorporated in a 10-gene signature that predicted biochemical recurrence for prostate cancer, and its expression level was upregulated in patients with a Gleason score ≥7 ( Wu et al, 2020 ). In contrast, there was a negative correlation between lymph node metastasis and NXPH1 in pancreatic cancer ( Jin and Tsai, 2016 ).…”

Synaptonemal complex proteins modulate the level of genome integrity in cancers

“…SYCE1 expression has been reported in lung adenocarcinoma and prostate cancer 40,41 . Although SYCE1 expression was not associated with the clinical characteristics of lung adenocarcinoma patients, 40 it was associated with a Gleason score of 7 or greater in prostate cancer, which is known to confer a higher risk for disease progression compared with a Gleason score of 6 or less 41 …”

“…SYCE1 expression has been reported in lung adenocarcinoma and prostate cancer. 40,41 Although SYCE1 expression was not associated with the clinical characteristics of lung adenocarcinoma patients, 40 it was associated with a Gleason score of 7 or greater in prostate cancer, which is known to confer a higher risk for disease progression compared with a Gleason score of 6 or less. 41 TA B L E 1 Ectopic expression of synaptonemal complex (SC) proteins in human cancers and its potential clinical significance SYCE2 expression has been reported in tumors of cervix, ovary, thyroid, uterus, kidney, and stomach, and in lymphomas.…”

“…40,41 Although SYCE1 expression was not associated with the clinical characteristics of lung adenocarcinoma patients, 40 it was associated with a Gleason score of 7 or greater in prostate cancer, which is known to confer a higher risk for disease progression compared with a Gleason score of 6 or less. 41 TA B L E 1 Ectopic expression of synaptonemal complex (SC) proteins in human cancers and its potential clinical significance SYCE2 expression has been reported in tumors of cervix, ovary, thyroid, uterus, kidney, and stomach, and in lymphomas. 42 Induction of SYCE2 expression was observed in DLD1 cells and the fibrosarcoma cell line HT1080 after treatment with the demethylating agent 5-azacytidine, 42 indicating that SYCE2 expression is also regulated by a demethylation-dependent process, as has been described for other cancer-testis antigens.…”

“…Although the SC proteins were first considered to be expressed only in meiotic cells, accumulating evidence shows that the SC proteins are ectopically and aberrantly expressed in various human cancers, as summarized in Table 1 15‐42 . This evidence suggests that the SC proteins are so‐called cancer/testis antigens, whose expression is normally limited to the germ cells but can be activated in cancer by a demethylation‐dependent process 43 …”