High Proliferation Rate in Mantle Cell Lymphoma Is Associated with p53 Mutations and Blastoid Morphology, but Not with 3'UTR Deficient Cyclin D1 mRNA or High Total Cyclin D1 mRNA Levels
J Slotta-Huspenina, I Koch, L de Leval, G Keller, K Bink, M Kremer, M Raffeld, F Fend, L Quintanilla-Martinez. Institute of Pathology, Technical University, Munich, Germany; Institute of Pathology, Helmholtz Center Munich, Munich, Germany; 3 Institute of Pathology, University of Tuebingen, Tuebingen, Germany; University of Lige, Lige, Belgium; National Cancer Institute, Bethesda
Background: The hallmark of MCL is overexpression of cyclin D1 (CyD1). Predominance of 3'UTR-deficient CyD1 mRNA and genomic 3'UTR alteration were found to be associated with a proliferation signature and poor prognosis. The aim of our study was to correlate the expression of CyD1 mRNA isoforms and genomic 3'UTR alterations, as well as secondary genetic alterations (p53, p16 and c-myc) with morphology and proliferation rate, as measured by MIB 1 staining in primary MCL.
Design: Paraffin-embedded tissue of 62 CyD1+MCL (10 blastoid and 52 typical) were analysed for expression of CyD1 3'UTR isoforms and genomic 3'UTR deletion by real-time RT-PCR and genomic qPCR, respectively. Findings were correlated with morphology and proliferation rate (MIB 1 pos <10%, 11-30%, >30%). P53 overexpression, as surrogate marker for p53 mutations was assessed by immunohistochemistry (>20%) and confirmed by DHPLC and sequencing analysis. P16 deletions and c-myc gene alterations were analysed by FISH.
Results: Predominance of CyD1 3'UTR deficient mRNA was found in 14 (22.6%) samples, including 4 with complete loss of the standard transcript, accompanied by genomic UTR deletion in two cases. P53 overexpression/ mutation was found in 12 cases. 3'UTR predominance was significantly associated with high total CyD1 mRNA levels (mean CyD1/TBP 87.2 vs 62.1, p=0.01) and blastoid morphology (5/10, p=0.04), but not with high proliferation rate (6/18, p=0.32). Instead, high proliferation rate (>30%) was significantly correlated with blastoid morphology (9/10, p<0.001) and p53 overexpression (11/12, p<0.001). In five highly proliferative cases without p53 mutations other secondary genetic alterations were investigated. In none of the cases p16 deletions or c-myc translocations were identified.
Conclusions: Predominance of the 3'UTR CyD1 deficient mRNA and CyD1 3'UTR deletion in MCL is associated with high total CyD1 mRNA level and blastoid morphology but not with high proliferation rate, as assessed by MIB 1 staining. In contrast, proliferation rate is highly associated with blastoid morphology and p53 overexpression.
Monday, March 9, 2009 1:15 PM
Platform Session: Section D, Monday Afternoon