The coding genome of splenic marginal zone lymphoma: activation of notch2 and other pathways regulating marginal zone development

Splenic marginal zone lymphoma (SMZL) is a B-cell malignancy of unknown pathogenesis and thus orphan of targeted therapies. By integrating whole-exome sequencing and copy-number analysis, here we show that the SMZL exome carries at least 30 non-silent gene alterations. Mutations of NOTCH2, a gene required for marginal-zone (MZ) development, represent the most frequent lesion in SMZL, accounting for ~20% of cases. All NOTCH2 mutations are predicted to cause impaired degradation of the NOTCH2 protein through the elimination of the C-terminal PEST domain, which is required for proteasomal recruitment. Among indolent B-cell lymphoproliferative disorders, NOTCH2 mutations are restricted to SMZL, thus representing a potential diagnostic marker for this lymphoma type. In addition to NOTCH2, other modulators or members of the NOTCH pathway are recurrently targeted by genetic lesions in SMZL, including NOTCH1, SPEN and DTX1. Additional altered genes suggest that deregulation of signaling pathways normally involved in MZ development (NF-κB and B-cell receptor signaling) represents a critical event in the pathogenesis of ~60% SMZL. These findings have direct implications for the treatment of SMZL patients given the availability of drugs that can target NOTCH, NF-κB and other pathways deregulated in this disease.