NOXA and PUMA expression add to clinical markers in predicting biochemical recurrence of prostate cancer patients in a survival tree model.
OBJECTIVE
To assess the expression of proapoptotic NOXA and PUMA in prostate tissues and delineate their association with prostate cancer (PCa) recurrence.


METHODS
Normal, prostatic intraepithelial neoplasia (PIN), hormone-sensitive (HS) PCa, and hormone-refractory (HR) PCa tissues were used to build tissue microarrays encompassing a total of 135 patients. Two observers assessed the intensity of NOXA and PUMA immunohistochemical staining using a composite color scale. One hundred and eighty recursive partitioning and regression tree (RPART) models were generated to predict biochemical recurrence (BCR) within HS cancer patients using NOXA, PUMA, and clinical parameters. Models were then ranked according to the integrated Brier score (IBS).


RESULTS
Increasing NOXA expression was associated with PCa progression, reaching the highest levels in HR PCa. Increased NOXA expression was observed in 68% of HS cancer patients and was predictive of BCR (LR = 8.64; P = 0.003). In contrast, PUMA expression was highest in HS cancer, and although 70% of HS cancer patients exhibited increased PUMA expression, PUMA alone could not predict the onset of BCR. Interestingly, the top-ranking RPART model generated [IBS = 0.107; 95% confidence interval (95% CI), 0.065-0.128] included surgical margin status and NOXA and PUMA expression, although recurrent prognostic classification schemes obtained in the top 10 models favored a survival tree model containing margin status, NOXA expression, and preoperative prostate-specific antigen (PSA) (IBS = 0.114; 95% CI, 0.069-0.142).


CONCLUSIONS
We conclude that NOXA and PUMA expression may be linked to PCa progression and propose further validation of a survival tree model including surgical margin status, NOXA expression, and preoperative PSA for predicting BCR.
Centre de Recherche du Centre Hospitalier de l'Université de Montréal and Institut du Cancer de Montréal, Québec, Canada.
Jean-Simon
JS
Diallo
Abdulhadi
A
Aldejmah
Abdelali Filali
AF
Mouhim
Benjamin
B
Péant
Mona Alam
MA
Fahmy
Ismaël Hervé
IH
Koumakpayi
Kanishka
K
Sircar
Louis R
LR
Bégin
Anne-Marie
AM
Mes-Masson
Fred
F
Saad
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D018450:Disease Progression; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D014408:Biomarkers, Tumor; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2