Genomic Profiling Reveals Alternative Genetic Pathways of Prostate Tumorigenesis

Abstract

Prostate cancer is clinically heterogeneous, ranging from indolent to lethal disease. Expression profiling previously defined three subtypes of prostate cancer, one (subtype-1) linked to clinically favorable behavior, and the others (subtypes-2 and -3) linked with a more aggressive form of the disease. To explore disease heterogeneity at the genomic level, we carried out array-based comparative genomic hybridization (array CGH) on 64 prostate tumor specimens, including 55 primary tumors and 9 pelvic lymph node metastases. Unsupervised cluster analysis of DNA copy number alterations (CNA) identified recurrent aberrations, including a 6q15-deletion group associated with subtype-1 gene expression patterns and decreased tumor recurrence. Supervised analysis further disclosed distinct patterns of CNA among gene-expression subtypes, where subtype-1 tumors exhibited characteristic deletions at 5q21 and 6q15, and subtype-2 cases harbored deletions at 8p21 (NKX3-1) and 21q22 (resulting in TMPRSS2-ERG fusion). Lymph node metastases, predominantly subtype-3, displayed overall higher frequencies of CNA, and in particular gains at 8q24 (MYC) and 16p13, and loss at 10q23 (PTEN) and 16q23. Our findings reveal that prostate cancers develop via a limited number of alternative preferred genetic pathways. The resultant molecular genetic subtypes provide a new framework for investigating prostate cancer biology and explain in part the clinical heterogeneity of the disease. [Cancer Res 2007;67(18):8504-10]

Genomic deletion of MAP3K7 at 6q12-22 is associated with early PSA recurrence in prostate cancer and absence of TMPRSS2:ERG fusions

“…1,2 Deletions of 6q12-22 have been described to occur in 22-62% of prostate cancers. [1][2][3][4][5] 6q12-22 deletions rank second in the list of frequent prostate cancer deletions after 8p11-21. 1,2 Published studies mapping the 6q12-22 deletion suggest a small commonly deleted region on 6q15 with a length of 3-4 megabases (Mb).…”

“…Some studies associated this alteration with unfavorable phenotype, 4 metastasis 16 or decreased tumor recurrence. 3,5 Others could not find clinically relevant associations or described associations with more benign tumor features. 5,17 These studies included patient cohorts of 24-95 cases.…”

“…3,5 Others could not find clinically relevant associations or described associations with more benign tumor features. 5,17 These studies included patient cohorts of 24-95 cases. To identify possible clinico-pathological associations of MAP3K7 deletions in prostate cancer, we analyzed a prostate cancer tissue microarray containing samples of 4699 patients.…”

Ezrin mediates c-Myc actions in prostate cancer cell invasion

“…PTEN is a tumor suppressor that antagonizes the oncogenic PI-3K/Akt pathway and is one of the most common genetic deletions observed in advanced PCa (Joshua et al, 2007;Lapointe et al, 2007). Taking advantage of the fact that LNCaP-FGC is a PTEN-deficient PCa cell line (Vlietstra et al, 1998), we overexpressed WT PTEN and an inactive variant (C124S mutant) and measured the effects of androgen on ezrin and c-Myc protein levels, as well as GSK-3b and Akt activities.…”

“…Metastatic progression of PCa is characterized by a set of preferred genetic lesions (Lapointe et al, 2007;Sun et al, 2007). Amplification of 8q24, the region containing the c-Myc gene, is the most commonly observed genetic alteration associated with PCa metastasis, being observed in approximately 50% of clinically presented metastatic tumors.…”