MYD88 somatic mutations in MALT lymphomas

Abstract

Extranodal marginal zone lymphoma (MZL) of mucosa-associated lymphoid tissue type (MALT lymphoma) is an indolent lymphoma that is found at a number of different extranodal anatomical sites and in total accounts for 7–8% of all non-Hodgkin (Bertoni et al, 2011). Recurrent chromosomal translocations and unbalanced genomic aberrations have been reported in MALT, many of which lead to activation of the nuclear factor (NF)-κB pathway (Bertoni et al, 2011). MYD88 is a central molecule in the cascade that activates NF-κB signalling after stimulation of either Toll-like, interleukin (IL) 1 and IL18 receptors (Ngo et al, 2011). The MYD88 gene is located at chromosome 3p22, a region commonly gained in MALT lymphomas (Rinaldi et al, 2011). MYD88 mutations were first described to occur almost exclusively in the activated B-cell like subtype (39%) of diffuse large B-cell lymphomas (Ngo et al, 2011), which are also characterized by NF-κB activation. Recurrent mutations were also described in 9% of gastric MALT lymphomas (Ngo et al, 2011). The vast majority of mutations, and all those observed in MALT lymphomas, determined a non-synonymous change at amino acid position 265 with a change from leucine to proline (L265P) (Ngo et al, 2011). Very recently, Xu et al (2011) identified the same MYD88 L265P change in 46/51 (90%) lymphoplasmacytic lymphomas (LPL), 87% with an IgM monoclonal protein (Waldenstrom Macroglobulinemia, WM), contrasting with 3/46 (6%) in MZLs, including 1/20 (5%) MALT lymphomas (Xu et al, 2011). These authors suggested that a L265P mutation could be used to differentiate LPL/WM from MZLs (Xu et al, 2011). With the aim of assessing the prevalence of MYD88 L265P mutations in MALT lymphomas, we studied 53 MALT lymphoma cases, previously characterized by genome-wide DNA profiling (Rinaldi et al, 2011). Informed consent was obtained in accordance with the Declaration of Helsinki following the procedures approved by the local ethical committees and institutional review boards of each participating institution. Whole genome-amplification (WGA) was performed as previously described (Mensah et al, 2012). MYD88 exon 5 underwent polymerase chain reaction (PCR) amplification using 5′-AGG GAG GACT GTG GAT GCA GTA CCA A -3′ and 5′-CTG CAG ACG TGT CTG TGA AGT T-3′, as forward and reverse primers (Morin et al, 2011), respectively. PCR products were sequenced as previously described (Mensah et al, 2012), and the sequence chromatograms were viewed with ChromasLite 2.01 (Technelysium Pty Ltd, Brisbane, Qld, Australia) and compared against GenBank NM_002468. Three out of the 53 (6%) of the MALT lymphoma cases revealed non-synonymous MYD88 mutations, all of which were verified using non-WGA DNA (Fig 1). Two cases harboured a T978C mutation causing the reported L265P substitution. Both of these cases presented with orbital adnexa involvement and no additional genomic lesions; one case had bone marrow involvement. One case of salivary gland MALT lymphoma, with trisomies of chromosomes 3 and 18, showed a novel interstitial 27bp deletion (c.1039_1065del) resulting in the loss of amino acids VCDYTNPCT (p.V286_T294del) that precede an internal inhibitory domain (Li et al, 2005; Ngo et al, 2011), which could become disrupted and allow an increased binding of MYD88 to IRAK1/IRAK4. Somatic mutations of MYD88 have been shown to activate down-stream signalling leading to the activation of both NF-κB but also JAK/STAT3 signalling (Ngo et al, 2011), providing a rationale for molecule-targeted pharmaceutical approaches in these patients. In conclusion, our data indicate that MYD88 is deregulated in a small subset of patients with MALT lymphoma. These MYD88 mutation-bearing patients, as well patients affected by LPL/WM (Xu et al, 2011) or by other indolent lymphoid tumours carrying similar mutations (Fabbri et al, 2011; Wang et al, 2011; Yan et al, 2012) will benefit from the development of new therapeutic strategies that target specific pathways irrespective of the lymphoma subtype. This work was supported by Oncosuisse grant OCS-02034-02-2007, Nelia and Amedeo Barletta Foundation (Lausanne, Switzerland) and Italian Association for Cancer Research (AIRC). FB conceived and designed the study. ZML, AR, AC and AAM performed analyses. MP, RDG, GB and EZ collected and characterized MZL samples. ZML, AC and FB interpreted the data and co-wrote the manuscript. All authors read and approved the final manuscript. All authors declare no conflict of interest.