Development and internal validation of a novel model and markers to identify the candidates for lymph node metastasis in patients with prostate cancer

Abstract

Background High-grade prostate cancer (PCa) has a poor prognosis, and up to 15% of patients worldwide experience lymph node invasion (LNI). To further improve the prediction lymph node invasion in prostate cancer, we adopted risk scores of the genes expression based on the nomogram in guidelines. Methods We analyzed clinical data from 320 PCa patients from the Cancer Genome Atlas database. Weighted gene coexpression network analysis was used to identify the genes that were significantly associated with LNI in PCa (n = 390). Analyses using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were performed to identify the activated signaling pathways. Univariate and multivariate logistic regression analyses were performed to identify the independent risk factors for the presence of LNI. Results We found that patients with actual LNI and predicted LNI had the worst survival outcomes. The 7 most significant genes (CTNNAL1, ENSA, MAP6D1, MBD4, PRCC, SF3B2, TREML1) were selected for further analysis. Pathways in the cell cycle, DNA replication, oocyte meiosis, and 9 other pathways were dramatically activated during LNI in PCa. Multivariate analyses identified that the risk score (odds ratio [OR] = 1.05 for 1% increase, 95% confidence interval [CI]: 1.04–1.07, P < .001), serum PSA level, clinical stage, primary biopsy Gleason grade (OR = 2.52 for a grade increase, 95% CI: 1.27–5.22, P = .096), and secondary biopsy Gleason grade were independent predictors of LNI. A nomogram built using these predictive variables showed good calibration and a net clinical benefit, with an area under the curve (AUC) value of 90.2%. Conclusions In clinical practice, the application of our nomogram might contribute significantly to the selection of patients who are good candidates for surgery with extended pelvic lymph node dissection.

Influence of Biopsy Gleason Score on the Risk of Lymph Node Invasion in Patients With Intermediate-Risk Prostate Cancer Undergoing Radical Prostatectomy

“…Nonetheless, it is noteworthy to consider that a contemporary investigation demonstrated that PLND in patients with >5% risk of LNI did not yield to better oncological survival outcome in patients with intermediate-and high-risk PCa, relative to non-performance of PLND (24). However, our results suggest that stratification according to ISUP grade in patients with intermediate-risk PCa predicts LNI for clinical considerations, as previous publications have also shown ISUP grade/Gleason score at biopsy in general to be an independent risk factor for LNI (26). In consequence, PLND should be performed in patients with higher ISUP/Gleason score at biopsy and might be omitted in selected patients with intermediate risk with ISUP grade 1.…”

Convergent network effects along the axis of gene expression during prostate cancer progression

“…Further, our network analysis is suggesting tumor mechanisms converging on genes that are known contributors to PCa tumor biology. For example, the PCa-associated gene SF3B2 [ 74 , 75 ] was only weakly amplified in some of the high-grade tumors (average log 2 FC = 0.016), and mRNA levels showed similarly small changes (average log 2 FC = 0.024). On the other hand, the SF3B2 protein levels were consistently and more strongly upregulated across tumors (average log 2 FC = 0.31), especially within the high-grade tumors (Additional file 1 : Fig.…”

ZNF92, an unexplored transcription factor with remarkably distinct breast cancer over-expression associated with prognosis and cell-of-origin

“…For example, overexpression of Fibrinogen C domain containing 1 (FIBCD1), which is a transmembrane endocytic receptor, correlates with poor prognosis in gastric and liver cancers 83 , 84 . Microtubule Associated Protein 6 (MAP6) Domain Containing 1 protein is implicated in lymph node metastasis in prostate cancer 85 , and the over-expression of Coiled-Coil Domain Containing 69 (CCDC69), which is scaffold protein involved in DNA replication and mitotic spindle formation, is associated with cisplatin-resistance ovarian cancer cells 86 .…”