Survival analysis of genome-wide gene expression profiles of prostate cancers identifies new prognostic targets of disease relapse.
Current models of prostate cancer classification are poor at distinguishing between tumors that have similar histopathological features but vary in clinical course and outcome. Here, we applied classical survival analysis to genome-wide gene expression profiles of prostate cancers and preoperative prostate-specific antigen (PSA) levels from each patient, to identify prognostic markers of disease relapse that provide additional predictive value relative to PSA concentration. Three of approximately 200 probesets showing strongest correlation with relapse were identified as the gene for the putative calcium channel protein, trp-p8, with loss of trp-p8 mRNA expression associated with a significantly shorter time to PSA relapse-free survival. We observed subsequently that trp-p8 is lost in the transition to androgen independence in a prostate cancer xenograft model and in prostate cancer tissue from patients treated preoperatively with antiandrogen therapy, suggesting that trp-p8 is androgen regulated, and its loss may be associated with more advanced disease. The identification of trp-p8 and other proteins implicated in the phosphatidylinositol signal transduction pathway that are associated with prostate cancer outcome, both here and in other published work, suggests an integral role for this pathway in prostate carcinogenesis. Thus, our findings demonstrate that multivariable survival analysis can be applied to gene expression profiles of prostate cancers with censored follow-up data and used to identify molecular markers of prostate cancer relapse with strong predictive power and relevance to the etiology of this disease.
Henshall
Susan M
SM
Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Darlinghurst, Sydney, New South Wales 2010, Australia.
Afar
Daniel E H
DE
Hiller
Jordan
J
Horvath
Lisa G
LG
Quinn
David I
DI
Rasiah
Krishan K
KK
Gish
Kurt
K
Willhite
Dorian
D
Kench
James G
JG
Gardiner-Garden
Margaret
M
Stricker
Phillip D
PD
Scher
Howard I
HI
Grygiel
John J
JJ
Agus
David B
DB
Mack
David H
DH
Sutherland
Robert L
RL
D000818:Animals; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016019:Survival Analysis; D014183:Transplantation, Heterologous