Notch1/2 mutations are recurrently found in Cyclin D1-Negative Sox11-Positive Mantle Cell Lymphoma

Abstract

Recurrent chromosomal alterations in Cyclin D1−/SOX11+ mantle cell lymphoma (MCL) were recently described, but other molecular alterations contributing to the pathogenesis of these MCL variant are not well known. CCND2 translocations are found in around half of these patients, but primary alterations in the remaining cases have not been identified. Mutations of NOTCH1, NOTCH2, MEF2B, BIRC3, WHSC1, ATM and TP53 are recurrent in Cyclin D1+ MCL, but their incidence in Cyclin D1− MCL is still unknown. Methods: Fifty-four Cyclin D1−/SOX11+ MCL were investigated by FISH, array CGH, gene expression profiling and quantitative PCR. We also performed Sanger sequencing of TP53, MEF2B, WHSC1, BIRC3, NOTCH1 and NOTCH2 mutational hot spots. Results: FISH screening detected CCND2 translocations in 26 Cyclin D1−/SOX11+ MCL cases (48%). Of note, two cases carried a break in one allele and high level amplification of the remaining allele. Analysis of IG genes revealed that CCND2-negative Cyclin D1− MCL do not carry aberrations affecting IGH, IGK and IGL genes with the exception of two cases that had IGH breaks and moderate levels of Cyclin D2 expression. The global genomic profile and the complexity of the 45 cyclin D1− SOX11+ MCL patients analysed by copy number arrays were similar to the conventional Cyclin D1+ MCL. Of note, cases without CCND2 translocation carried significantly more frequent losses of 1p21.3-p12, whereas 3q24-qter gains and losses of 3p14.2-p12.2 were more frequently found in the CCND2-translocation positive cases (p = 0.04). Gene expression profiles of Cyclin D1− SOX11+ MCL were similar to conventional Cyclin D1+ MCL.