title: 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.
authors: Department of Pathology, Stanford University, Stanford, California, USA.
authors: Jacques
authors: J
authors: Lapointe
authors: Chunde
authors: C
authors: Li
authors: Craig P
authors: CP
authors: Giacomini
authors: Keyan
authors: K
authors: Salari
authors: Stephanie
authors: S
authors: Huang
authors: Pei
authors: P
authors: Wang
authors: Michelle
authors: M
authors: Ferrari
authors: Tina
authors: T
authors: Hernandez-Boussard
authors: James D
authors: JD
authors: Brooks
authors: Jonathan R
authors: JR
authors: Pollack
mesh_terms: D002869:Chromosome Aberrations; D016000:Cluster Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D018628:Gene Dosage; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology
chemical_list: D004273:DNA, Neoplasm