Genetic markers associated with early cancer-specific mortality following prostatectomy.

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.

Germ-line sequence variants of PTEN do not have an important role in hereditary and non-hereditary prostate cancer susceptibility.

PTEN (phosphatase and tensin homolog deleted on chromosome 10) functions as a major tumor suppressor gene and is frequently deleted in different types of tumors including prostate cancer (PCa). It was hypothesized that germ-line genetic changes of PTEN affect susceptibility to PCa. Both common (with a minor allele frequency 5%) and rare (with a minor allele frequency <5%) germ-line variants of PTEN were comprehensively evaluated. A total of 15 germ-line variants were identified by re-sequencing the PTEN gene, including 5' untranslated region, all nine exons, exon-intron junctions and 3' untranslated region, in 188 probands of hereditary prostate cancer (HPC) families recruited from Johns Hopkins Hospital. Two microsatellite markers surrounding PTEN were used to test the co-segregation of 10 rare variants, which may give rise to highly penetrance in HPC. Two common single nucleotide polymorphisms (SNPs) were evaluated in the 188 HPC families using a family-based association study approach. To study low penetrant SNPs in PCa susceptibility, 33 SNPs covering PTEN were selected from the whole genome-wide association studies (GWAS) from our available case-control studies in Sweden (Cancer of the Prostate in Sweden (CAPS)) and the publicly available cancer genetic markers of susceptibility (CGEMS) study. Germ-line copy-number variations (CNVs) in PTEN were assessed in CAPS. Co-segregation of germ-line variants and PCa was not observed among HPC families and no significant differences in the allele frequencies were observed in sporadic cases and controls, aggressive and non-aggressive PCa (P>0.05). These results suggest that germ-line variants in PTEN do not have an important role in PCa susceptibility.