Molecular Subsets of Mantle Cell Lymphoma Defined by the IGHV Mutational Status and SOX11 Expression Have Distinct Biologic and Clinical Features

Abstract

Mantle cell lymphoma (MCL) is a heterogeneous disease with most patients following an aggressive clinical course while others have an indolent behavior. We performed an integrative and multidisciplinary analysis of 177 MCL to determine whether the immunogenetic features of the clonotypic B cell receptors may identify different subsets of tumors. ‘Truly unmutated’ (100% identity) IGHV genes were found in 24% cases, 40% were ‘minimally/borderline mutated’ (99.9-97%), 19% ‘significantly mutated’ (96.9-95%) and 17% ‘hypermutated’ (<95%). Tumors with high (≥97%) or low (<97%) mutational load used different IGHV genes and their gene expression profiles were also different for several gene pathways. A gene set enrichment analysis showed that MCL with high and low IGHV mutations were enriched in memory and naïve B-cell signatures, respectively. Furthermore, the highly mutated tumors displayed less genomic complexity, were preferentially SOX11 negative, and showed more frequently non-nodal disease. The best cut-off of germline identity of IGHV genes to predict survival was 3%. Patients with high and low mutational load had significant different outcome with 5-year overall survival of 59% and 40%, respectively (P=0.004). Nodal presentation and SOX11 expression also predicted for poor overall survival. In a multivariate analysis, IGHV gene status and SOX11 expression were independent risk factors. In conclusion, these observations suggest the idea that MCL with mutated IGHV, SOX11 negativity, and non-nodal presentation correspond to a subtype of the disease with more indolent behavior.

Acquired TERT promoter mutations stimulate TERT transcription in mantle cell lymphoma

“…Such an aggressive feature relates to a high number of recurrent secondary chromosomal aberrations and different molecular mechanisms causing gene deregulation. The transcription factor SOX11 (SRY [sex determining region Y]-box 11) has been found aberrantly expressed in most aggressive MCL patients, being considered a reliable biomarker in this pathology [2]. This gene is commonly associated with embryonic neurogenesis and tissue remodeling, and is not expressed under normal conditions in any adult normal tissue [3].…”

Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

“…Paradoxically, a subset of patients follows an indolent clinical evolution with stable disease even in the absence of chemotherapy (6,7). This favorable behavior has been associated with IGHV-mutated (8,9) and lack of expression of SOX11 (10, 11), a transcription factor highly specific of MCL that contributes to the aggressive behavior of this tumor (12). However, the molecular mechanisms responsible for this clinical heterogeneity are not well understood.…”

Primary mantle cell lymphoma of tonsil: Case report

“…Иницијални догађај се одиграва у пре-B ћелијама коштане сржи и праћен је кретањем у два правца молекуларних измена 12,13 . Ове ћелије су генетски стабилне, СОX11 експресија је негативна или ниска и тумор има тенденцију дисеминације у периферну крв и слезину.…”