19 research outputs found
Construction of a set of novel and robust gene expression signatures predicting prostate cancer recurrence
We report here numerous novel genes and multiple new signatures which robustly predict prostate cancer (PC) recurrence. We extracted 696 differentially expressed genes relative to a reported PC signature from the TCGA dataset (nĀ =Ā 492) and built a 15āgene signature (SigMuc1NW) using Elasticānet with 10āfold crossāvalidation through analyzing their expressions at 1.5 standard deviation/SD below and 2Ā SD above a population mean. SigMuc1NW predicts biochemical recurrence (BCR) following surgery with 56.4% sensitivity, 72.6% specificity, and 63.24 median months disease free (MMDF) (PĀ =Ā 1.12eā12). The prediction accuracy is improved with the use of SigMuc1NW's cutpoint (PĀ =Ā 3eā15) and is further enhanced (sensitivity 67%, specificity 75.7%, MMDF 45.2, PĀ =Ā 0) when all 15 genes were analyzed through their cutpoints instead of their SDs. These genes individually associate with BCR using either SD or cutpoint as the cutoff points. Eight of 15 genes are individual risk factors after adjusting for age at diagnosis, Gleason score, surgical margin, and tumor stage. Eleven of 15 genes are novel to PC. SigMuc1NW discriminates BCR with timeādependent AUC (tAUC) values of 76.6% at 11.5Ā months (76.6%ā11.5Ā m), 73.8%ā22.3Ā m, 78.5%ā32.1Ā m, and 76.4%ā48.4Ā m. SigMuc1NW is correlated with adverse features of PC, high Gleason scores (odds ratio/OR 1.48, PĀ <Ā 2eā16), and advanced tumor stages (OR 1.33, PĀ =Ā 4.37eā13). SigMuc1NW remains an independent risk factor of BCR (HR 2.44, 95% CI 1.53ā3.87, PĀ =Ā 1.62eā4) after adjusting for age at diagnosis, Gleason score, surgical margin, and tumor stage. In an independent PC (MSKCC) cohort (nĀ =Ā 140), these 15 genes were altered in PC vs normal tissue, metastatic PCs vs primary PCs, and recurrent PCs vs nonrecurrent PCs. Importantly, a 10āgene subsignature SigMuc1NW1 predicts BCR in MSKCC (PĀ =Ā 3.11eā15) and TCGA (PĀ =Ā 3.13eā12); SigMuc1NW1 discriminates BCR at 18.4Ā m with tAUC as 82.5%. Collectively, our analyses support SigMuc1NW as a novel and robust signature in predicting BCR of PC