Genetic markers associated with early cancer-specific mortality following prostatectomy

Abstract

Background: This study sought to identify novel effectors and markers of localized but potentially life-threatening prostate cancer (PCa), by evaluating chromosomal copy number alterations (CNAs) in tumors from patients who underwent prostatectomy and correlating these with clinicopathologic features and outcome.

Methods: CNAs in tumor DNA samples from 125 patients in the discovery cohort who underwent prostatectomy were assayed with high-resolution Affymetrix 6.0 single-nucleotide polymorphism microarrays and then analyzed using the Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm.

Results: The assays revealed 20 significant regions of CNAs, 4 of them novel, and identified the target genes of 4 of the alterations. By univariate analysis, 7 CNAs were significantly associated with early PCa-specific mortality. These included gains of chromosomal regions that contain the genes MYC, ADAR, or TPD52 and losses of sequences that incorporate SERPINB5, USP10, PTEN, or TP53. On multivariate analysis, only the CNAs of PTEN (phosphatase and tensin homolog) and MYC (v-myc myelocytomatosis viral oncogene homolog) contributed additional prognostic information independent of that provided by pathologic stage, Gleason score, and initial prostate-specific antigen level. Patients whose tumors had alterations of both genes had a markedly elevated risk of PCa-specific mortality (odds ratio = 53; 95% CI = 6.92-405, P = 1 × 10(-4)). Analyses of 333 tumors from 3 additional distinct patient cohorts confirmed the relationship between CNAs of PTEN and MYC and lethal PCa.

Conclusions: This study identified new CNAs and genes that likely contribute to the pathogenesis of localized PCa and suggests that patients whose tumors have acquired CNAs of PTEN, MYC, or both have an increased risk of early PCa-specific mortality.

Fig. 1

Genomic identification of significant targets in cancer (GISTIC) using segmented DNA copy number data from the tumor genomes in the JHH cohort. Using a q-value of 0.01, a join segment size of 80, and a threshold for copy number amplification/deletion of 0.12, we identified 20 significant regions, including 15 deletions (left blue panel) and five amplifications (right red panel). Left and right Y axes represent cytoband. Vertical green line depicts FDR of 0.01. Top and bottom X axes represent G-score and q-value, respectively. * Novel regions and genes identified; ‡ refined regions with new genes identified; † known regions and genes confirmed in this study.