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Haematologica 2020 Volume 105(3):754-764
Non-Hodgkin Lymphoma
Highly sensitive and specific in situ hybridization assay for quantification of SOX11 mRNA in mantle cell lymphoma reveals association of TP53 mutations with negative and low SOX11 expression
Birgit Federmann, Leonie Frauenfeld, Helga Pertsch, Vanessa Borgmann, Julia Steinhilber, Irina Bonzheim, Falko Fend and Leticia Quintanilla-Martinez
Institute of Pathology and Neuropathology, Comprehensive Cancer Center and University Hospital Tübingen, Eberhard-Karls-University of Tübingen, Tübingen, Germany
ABSTRACT
SOX11 is a valuable marker to identify biologically and clinically rele- vant groups of mantle cell lymphoma such as cyclin D1 negative and leukemic non-nodal mantle cell lymphoma (MCL). We aimed to estab- lish a sensitive in situ hybridization analysis of SOX11 mRNA allowing its quantification within the histopathological context and compare it with immunohistochemistry and real-time quantitative reverse transcription- PCR (RT-qPCR). Furthermore, TP53 status was correlated with SOX11 mRNA levels. Sixty-six cases were investigated; 58 conventional mantle cell lymphomas (cMCL), including six cyclin D1 negative (46 classic, 12 blas- toid) and eight leukemic non-nodal mantle cell lymphomas (nnMCL). RNAscope was used for the in situ hybridization and the results scored as 0 to 4. MCL cases with SOX11 positivity by immunohistochemistry (IHC) were positive by RNA in situ hybridization (RNAscope) but with different scores. RT-qPCR showed a good correlation with the median of the grouped scores but had a wide variation in individual cases. The SOX11 negative leukemic non-nodal mantle cell lymphomas were also negative by RNAscope. TP53 was mutated in 13/63 (21%) cases, including 5/7 (71%) leukemic non-nodal and 8/56 (14%) cMCL. Interestingly, of the TP53 mutated cases, nine were in the RNAscope negative/low SOX11 group (9/15; 60%) and four in the high SOX11 group (4/36; 11%) (P=0.0007). In conclusion, RNAscope is a reliable method to evaluate SOX11 mRNA lev- els. This study demonstrates the broad range of SOX11 mRNA levels in MCL. An important finding is the significant correlation of TP53 mutations with negative/low SOX11 mRNA level both in leukemic nnMCL and cMCL.
Introduction
MCL is a mature B-cell neoplasm, which accounts for 3-10% of all non-Hodgkin´s lymphomas. The genetic hallmark of MCL is the t(11;14)(q13;q32) chromosomal translocation that juxtaposes the immunoglobulin heavy chain gene (IGH) on 14q32 to the CCND1 gene on 11q13 leading to a deregulated overexpression of CCND1 mRNA and cyclin D1 protein, in 95% of the cases.1,2 The existence of cyclin D1 neg- ative MCL (D1-MCL) was demonstrated by gene expression profile3 (GEP) and fur- ther studies based on real-time quantitative RT-qPCR and fluorescence in situ hybridization (FISH) analysis demonstrated that the majority of these cases carry a CCDN2 translocation4-7 and few cases have a CCND3/IGH or IGK/IGL rearrange- ment.8,9 Importantly, cyclin D1 positive and negative MCL have the same morpho- logic, pathologic, clinical and molecular features and are characterized by the expres- sion of the transcription factor Sex determining region Y-box 11 (SOX11).10 Due to the positivity of SOX11 in D1-MCL6,11,12 and the negativity in other mature B-cell neo- plasms, the immunohistochemical analysis of SOX11 has become a valuable marker for the identification of the different subsets of MCL.13 Although MCL has been tra-
Correspondence:
LETICIA QUINTANILLA-MARTINEZ
leticia.quintanilla-fend@med.uni-tuebingen.de
Received: March 11, 2019. Accepted: July 10, 2019. Pre-published: July 11, 2019.
doi:10.3324/haematol.2019.219543
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