Molecular Genetics of Mantle Cell Lymphoma

Abstract

Mantle cell lymphoma (MCL) is an aggressive neoplasm considered incurable with current therapies. Both the Cyclin D1 translocation and the profile of genomic alterations are well known but the landscape of somatic mutations has only been recently characterised. Overall, numerical and structural alterations, amplifications, homozygous deletions, and somatic mutations affect components of the cell cycle regulation, deoxyribonucleic acid (DNA) damage response, cell survival pathways, NOTCH and NFκB pathways, and the chromatin modification machinery. These alterations are potentially involved in the pathogenesis, progression and poor response to treatment of these lymphomas. In this review, the pathogenetic mechanisms of MCL, and how their better knowledge may help in offering new perspectives for the treatment of patients providing potential targets for individualised therapeutic intervention is discussed.

Key Concepts:

  • MCL is an aggressive B‐cell lymphoma.

  • A subset of patients follows an indolent clinical course.

  • Translocations of CCND1 (or CCND2) are the primary genetic alterations.

  • MCL have a very specific profile of secondary chromosomal gains and losses.

  • Several crucial genes are targeted by homozygous deletions and amplifications.

  • MCL SOX11‐positive with unmutated‐IGHV show high genomic complexity and worse prognostic compared to SOX11‐negative with mutated‐IGHV.

  • The different molecular and clinical subtypes of MCL have a different mutation distribution pattern.

  • The main pathways affected by molecular alterations in MCL are cell cycle regulation, DNA damage response, cell survival pathways, NOTCH and NFκB pathways, and chromatin modification machinery.

  • Identifying molecular mechanisms that contribute to MCL pathogenesis and progression may offer potential targets for the management of the patients.

Keywords: Mantle cell lymphoma; hallmark translocation; copy number alteration; homozygous deletion; CNN‐LOH; target gene; pathway; mutation; targeted treatment; prognosis

Figure 1.

Recurrent HD in MCL. (a) Frequencies of recurrent HD in 10 series of MCL analysed by SNP‐ or CGH‐arrays. Each colour bar represents a single study in MCL cases, except Beà et al. () in which the 10 MCL cell lines are represented separately. (b) The most frequent HD in MCL is located in 9p21.3. The entire chromosome 9 of 8 primary MCL tumours is represented horizontally from pter (left) to qter (right). In the raw data of SNP6.0 array, the regions with loss are represented in red and gains in blue. The deletions of chromosome 9 could vary from monosomy of whole chromosome 9, discontinuous losses of 9q and 9p, loss of whole p arm, or discontinuous losses at 9p arm. Invariably, all losses of 9p involve 9p21, and in an important percentage of cases the deletion is homozygous, with the minimal deleted region (MDR) covering CDKN2A and CDKN2B. Usually, the deletion of both alleles has different sizes: a large and a more focal loss centred at CDKN2A, CDKN2B, which result in complete biallelic inactivation (Bea et al., ; Flordal et al., ; Halldorsdottir et al., ; Hartmann et al., ; Kawamata et al., ; Kohlhammer et al., ; Salaverria et al., ; Tagawa et al., ; Vater et al., ).

Figure 2.

Recurrent amplifications in MCL. (a) Frequencies of amplifications in 10 series of MCL analysed by SNP‐ or CGH‐arrays. Each colour bar represents a single study with primary MCL cases, except Beà et al. () which is represented separately. (b) The more frequent amplification in primary MCL is 13q31.2, with the minimal amplified region (MAR) spanning the cluster or miR17–92 locus (microRNA encoded in an intronic region of the MIR17HG gene). The entire chromosome 13 of 6 primary MCL tumours is represented horizontally from cen (left) to qter (right). In the raw data of SNP6.0 array, the regions with loss are represented in red and gains in blue. The amplifications of 13q31 are usually accompanied by losses at both sides, suggesting their origin due to breakage‐fusion breaks cycles (Bea et al., ; Flordal et al., ; Halldorsdottir et al., ; Hartmann et al., ; Kawamata et al., ; Kohlhammer et al., ; Salaverria et al., ; Tagawa et al., ; Vater et al., ).

Figure 3.

Examples of copy‐number neutral loss of heterozygosity (CNN‐LOH) regions in MCL. (a) Chromosome 6 of a tumour (green) and its corresponding constitutional DNA (black) of an MCL patient showing a somatic 6p CNN‐LOH only in the tumour sample. Chromosome 6 is represented horizontally from pter (left) to qter (right). The top panel represents the CNN‐LOH (solid rectangles). The middle panel represents the allelic ratio, only two states (AA, BB) are detected in the 6p CNN‐LOH region as compared to the three states detected in the normal regions (AA, BB, AB). The bottom panel represents the copy number status, which has no loss in the CNN‐LOH region. *The tumour DNA has also a small somatic 6p interstitial loss. (b) Example of an acquired 17p CNN‐LOH in the tumour DNA of a MCL patient. The TP53 gene is the target of this CNN‐LOH, in this case an homozygous mutation of TP53 has been detected as an alternative phenomenon to the more frequent pattern of loss of one allele and mutation of the remaining allele.

Figure 4.

Somatic mutated genes in MCL. (a) Frequencies of the recurrently mutated genes deposited in COSMIC database, and reported in RNA‐seq and whole‐genome/whole‐exome studies (including the validation series of each study) are represented in different colour bars. (b) Number of cases studied and percentage of mutations of each gene. (c) Distribution of somatic mutations detected by whole‐exome and Sanger sequencing in a series of tumours characterised molecularly, and represented within SOX11‐positive and SOX11‐negative subgroups. In a few cases, SOX11 could not be determined (ND).

Figure 5.

Schematic integration of the most frequent MCL somatic copy number alterations and mutations in MCL. Each column represents a single primary MCL tumour. In the upper panel the IGHV mutational status (unmutated‐IGHV in purple), SOX11 expression (positive in green); in the middle panel the frequent losses, 17p, 11q and 9p (in red), 17p CNN‐LOH was also considered as ‘altered’, and the frequent gains 8q and 3q (in blue), unaltered regions were represented in grey and cases with no information available are left blank. In the lower panel, the presence of the recurrent mutations (solid black dot represents mutation). The right side of the figure shows the subgroup of clinically indolent MCL, with mutated‐IGHV, negative SOX11 expression, no copy number alterations and no mutations in the genes analysed.

Figure 6.

Hypothetical model of molecular pathogenesis in MCL. Stepwise progression of MCL from the initial oncogenic translocation of CCND1 (or CCND2 in a small subset of cases) to the clinically relevant disease, with acquisition of further genetic alterations that target important genes of the cell cycle, DNA damage response pathway, BCR signalling, NOTCH signalling and chromatin modifiers. The two subsets of MCL with the particular molecular characteristics, genomic gains and losses, mutations and clinical profile were indicated.

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Navarro, Alba, and Beà, Sílvia(Jun 2014) Molecular Genetics of Mantle Cell Lymphoma. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025234]