The impact of cyclin D1 mRNA isoforms, morphology and p53 in mantle cell lymphoma: p53 alterations and blastoid morphology are strong predictors of a high proliferation index
Julia Slotta-Huspenina,
Ina Koch,
Laurence de Leval,
Gisela Keller,
Margit Klier,
Karin Bink,
Marcus Kremer,
Mark Raffeld,
Falko Fend,
Leticia Quintanilla-Martinez
Affiliations
Julia Slotta-Huspenina
1Institute of Pathology, Technical University Munich, Munich, Germany
Ina Koch
1Institute of Pathology, Technical University Munich, Munich, Germany
Laurence de Leval
2Department of Pathology, CHU Sart Tilman, University of Liege, Liege, Belgium
Gisela Keller
1Institute of Pathology, Technical University Munich, Munich, Germany
Margit Klier
1Institute of Pathology, Technical University Munich, Munich, Germany
Karin Bink
3Institute of Pathology, Helmholtz Center Munich, Neuherberg, Germany
Marcus Kremer
1Institute of Pathology, Technical University Munich, Munich, Germany
Mark Raffeld
4Hematopathology Section, Laboratory of Pathology, NCI, NIH, Bethesda, MD, USA
Falko Fend
5Institute of Pathology and Comprehensive Cancer Center, Eberhard-Karls-University, Tübingen, Germany
Leticia Quintanilla-Martinez
5Institute of Pathology and Comprehensive Cancer Center, Eberhard-Karls-University, Tübingen, Germany
Background Mantle cell lymphoma is a clinically heterogeneous disease characterized by overexpression of cyclin D1 protein. Blastoid morphology, high proliferation, and secondary genetic aberrations are markers of aggressive behavior. Expression profiling of mantle cell lymphoma revealed that predominance of the 3’UTR-deficient, short cyclin D1 mRNA isoform was associated with high cyclin D1 levels, a high “proliferation signature” and poor prognosis.Design and Methods Sixty-two cases of mantle cell lymphoma were analyzed for cyclin D1 mRNA isoforms and total cyclin D1 levels by real-time reverse transcriptase polymerase chain reaction, and TP53 alterations were assessed by immunohistochemistry and molecular analysis. Results were correlated with proliferation index and clinical outcome.Results Predominance of the short cyclin D1 mRNA was found in 14 (23%) samples, including four with complete loss of the standard transcript. TP53 alterations were found in 15 (24%) cases. Predominance of 3’UTR-deficient mRNA was significantly associated with high cyclin D1 mRNA levels (P=0.009) and more commonly found in blastoid mantle cell lymphoma (5/11, P=0.060) and cases with a proliferation index of >20% (P=0.026). Both blastoid morphology (11/11, P
