Comparative analyses of chromosome alterations in soft-tissue metastases within and across patients with castration-resistant prostate cancer.
Androgen deprivation is the mainstay of therapy for progressive prostate cancer. Despite initial and dramatic tumor inhibition, most men eventually fail therapy and die of metastatic castration-resistant (CR) disease. Here, we characterize the profound degree of genomic alteration found in CR tumors using array comparative genomic hybridization (array CGH), gene expression arrays, and fluorescence in situ hybridization (FISH). Bycluster analysis, we show that the similarity of the genomic profiles from primary and metastatic tumors is driven by the patient. Using data adjusted for this similarity, we identify numerous high-frequency alterations in the CR tumors, such as 8p loss and chromosome 7 and 8q gain. By integrating array CGH and expression array data, we reveal genes whose correlated values suggest they are relevant to prostate cancer biology. We find alterations that are significantly associated with the metastases of specific organ sites, and others with CR tumors versus the tumors of patients with localized prostate cancer not treated with androgen deprivation. Within the high-frequency sites of loss in CR metastases, we find an overrepresentation of genes involved in cellular lipid metabolism, including PTEN. Finally, using FISH, we verify the presence of a gene fusion between TMPRSS2 and ERG suggested by chromosome 21 deletions detected by array CGH. We find the fusion in 54% of our CR tumors, and 81% of the fusion-positive tumors contain cells with multiple copies of the fusion. Our investigation lays the foundation for a better understanding of and possible therapeutic targets for CR disease, the poorly responsive and final stage of prostate cancer.
Divisions of Human Biology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, USA.
Ilona N
IN
Holcomb
Janet M
JM
Young
Ilsa M
IM
Coleman
Keyan
K
Salari
Douglas I
DI
Grove
Li
L
Hsu
Lawrence D
LD
True
Martine P
MP
Roudier
Colm M
CM
Morrissey
Celestia S
CS
Higano
Peter S
PS
Nelson
Robert L
RL
Vessella
Barbara J
BJ
Trask
D000368:Aged; D000369:Aged, 80 and over; D002869:Chromosome Aberrations; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D018628:Gene Dosage; D020869:Gene Expression Profiling; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D012983:Soft Tissue Neoplasms / Q000235:genetics* / Q000556:secondary*
D015514:Oncogene Proteins, Fusion; C515553:TMPRSS2-ERG fusion protein, human