Increased expression of the tumor suppressor PLZF is a continuous predictor of long-term survival in malignant melanoma patients.
Promyelocytic leukemia zinc finger (PLZF) is a transcriptional repressor and tumor suppressor inhibiting melanoma cell growth in vitro and in vivo in animal models. In this study, we analyzed the impact of in vivo primary tumor gene expression of PLZF on the long-term survival of malignant melanoma patients. PLZF expression was assessed by using DNA microarray and real-time polymerase chain reaction analysis of 41 primary malignant melanomas from patients with a defined histology and a close to 20-year clinical follow-up, of 29 melanoma metastases, and of 6 different melanoma cell lines. Kaplan-Meier survival analyses, log-rank statistics and Cox regression analysis were employed to identify the impact of PLZF expression on long-term survival. We detected PLZF expression in 92% of primary melanoma tumors in vivo but not in melanoma cell lines in vitro. By univariate analysis, we identified: (1) PLZF mRNA expression < or = 10,000 mRNA copies/mug total tumor RNA, (2) Breslow tumor thickness >4 mm, and (3) American Joint Committee on Cancer stages IIC, IIIB, IIIC, and IV as statistically significant pretreatment risk factors. We defined a continuous prognostic index (i.e., risk score) for primary melanoma patients based on the regression coefficient of PLZF mRNA expression. Applying a cutpoint to the prognostic index at - 1.65, patients were assigned to one of two risk groups: low-risk patients (n = 28) with a median overall survival of 79 months (5-year survival of 61%) and high-risk patients (n = 13) with a median overall survival of 32 months (5-year survival of 23%) (p < 0.05). This is the first time that PLZF mRNA expression has been linked to a prognostic model for primary malignant melanoma patients to derive prognostic groups for clinical purposes (e.g., improved melanoma immunotherapies).
Brunner
Georg
G
Fachklinik Hornheide an der Westfälischen Wilhelms-Universität Münster, Münster, Germany.
Reitz
Martina
M
Schwipper
Volker
V
Tilkorn
Hubertus
H
Lippold
Andrea
A
Biess
Brigitte
B
Suter
Ludwig
L
Atzpodien
Jens
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D045744:Cell Line, Tumor; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008297:Male; D008545:Melanoma / Q000175:diagnosis* / Q000235:genetics*; D008875:Middle Aged; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis / Q000706:statistics & numerical data; D011237:Predictive Value of Tests; D011379:Prognosis; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D016016:Proportional Hazards Models; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000706:statistics & numerical data; D013997:Time Factors
D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; C092037:ZBTB16 protein, human