The coding genome of splenic marginal zone lymphoma: activation of <i>NOTCH2</i> and other pathways regulating marginal zone development

Rossi, Davide; Трифонов, Владимир; Fangazio, Marco; Bruscaggin, Alessio; Rasi, Silvia; Spina, Valeria; Monti, Sara; Vaisitti, Tiziana; Arruga, Francesca; Famà, Rosella; Ciardullo, Carmela; Greco, Mariangela; Cresta, Stefania; Piranda, Daniela; Holmes, Antony B.; Fabbri, Giulia; Messina, Monica; Rinaldi, Andrea; Wang, Jiguang; Agostinelli, Claudio; Piccaluga, Pier Paolo; Lucioni, Marco; Tabbò, Fabrizio; Serra, Roberto; Franceschetti, Silvia; Deambrogi, Clara; Daniele, Giulia; Gattei, Valter; Marasca, Roberto; Facchetti, Fabio; Arcaini, Luca; Inghirami, Giorgio; Bertoni, Francesco; Pileri, Stefano; Deaglio, Silvia; Foà, Robin; Dalla‐Favera, Riccardo; Pasqualucci, Laura; Rabadán, Raúl; Gaïdano, Gianluca

doi:10.1084/jem.20120904

Cited by 350 publications

(371 citation statements)

References 62 publications

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“…Similar activating mutations have been recently described in splenic marginal zone lymphomas and in NOTCH1 in aggressive CLL and MCL (37,38). These findings prompted us to expand the study of NOTCH2 and NOTCH1 mutations in MCL and found their presence in 5.2% and 4.7% of the tumors, respectively.…”

Section: Discussionsupporting

confidence: 76%

“…Thus, NOTCH1 mutations have been found in CLL (18,26) whereas NOTCH2 is mutated in splenic marginal zone lymphomas (37,38); however, none of these tumors carry mutations in both NOTCH genes as observed in MCL. In addition, MLL2 and MEF2B mutations are shared with DLBCL (31-33) but are uncommon in CLL, whereas MCL has frequent mutations of ATM and BIRC3 that are also frequent in CLL (39) but uncommon in DLBCL.…”

Section: Discussionmentioning

confidence: 99%

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Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

Beà

Valdés-Mas

Navarro

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

468

361

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Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1, MLL2, and MEF2B. We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.next-generation sequencing | cancer genetics | cancer heterogeneity M antle cell lymphoma (MCL) is a mature B-cell neoplasm characterized by the t(11;14)(q13;q32) translocation leading to the overexpression of cyclin D1 (1). CCND1 is a weak oncogene that requires the cooperation of other oncogenic events to transform lymphoid cells (2). Molecular studies have identified alterations in components of the cell-cycle regulation, DNA damage response, and cell survival pathways (3, 4), but the profile of mutated genes contributing to the pathogenesis of MCL and cooperating with CCND1 is not well defined (1). Most MCL cases have a rapid evolution and an aggressive behavior with an unfavorable outcome with current therapies (5). 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.To gain insight into the molecular pathogenesis of MCL we performed whole-genome sequencing (WGS) and whole-exome sequencing (WES) of 29 MCL and further investigated mutated genes in an expanded series of patients. We also analyzed the subclonal heterogeneity of the tumors and their modulation during the evolution of the disease. Results Landscape of Mutations in MCL.We performed WGS and WES of 4 and 29 MCL, respectively. These patients were re...

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

Beà

Valdés-Mas

Navarro

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

468

361

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“…Most cases (40%; 95% CI: 19-64%; n = 6/15) utilized the IGHV4-34 gene and expressed mutated immunoglobulins (80%; 95% CI: 54-93%; n = 12/15) (Table SI). Overall, this clinical picture is consistent with that of the CBL-MZ cases described by Xochelli et al (2014).Mutually exclusive lesions of genes belonging to the physiological programme of MZ differentiation occurred in 37% (95% CI: 18-61%; n = 6/16) of CBL-MZ cases (Fig 1), a prevalence that did not significantly differ from that observed in SMZL (P = 0Á154) (Rossi et al, 2012). NOTCH2 mutations occurred in 13% (95% CI: 2-37%; n = 2/16) of cases, MYD88 mutations in 25% (95% CI: 9-49%; n = 4/16), and TNFAIP3 and CD79B mutations in 6% (95% CI: 0-30%; n = 1/16) each (Fig 1).…”

supporting

confidence: 87%

Molecular lesions of signalling pathway genes in clonal B‐cell lymphocytosis with marginal zone features

et al. 2014

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Molecular lesions of signalling pathway genes in clonal B-cell lymphocytosis with marginal zone featuresClonal B-cell expansions whose immunophenotype is consistent with marginal zone (MZ) lymphoma, but presenting with isolated lymphocytosis in the absence of splenomegaly or lymph node enlargements, cannot be assigned to any of the entities recognized by the World Health Organization (WHO) classification of haematological malignancies (Swerdlow et al, 2008). After reviewing the clinico-pathological features of such cases, Xochelli et al (2014) proposed that these lymphoproliferations: (i) may represent the early stage of a splenic marginal zone lymphoma (SMZL) or of a splenic B-cell lymphoma/leukaemia unclassifiable (SLLU); and (ii) should be classified as a provisional entity, termed clonal B-cell lymphocytosis with marginal zone features (CBL-MZ) in future classifications of mature B-cell tumours.Along with clinico-pathological features, the WHO classification also utilizes genetic data to define distinct and provisional entities (Swerdlow et al, 2008). If CBL-MZ are to be considered the early stage of SMZL, they should share a common genetic profile with this lymphoma, including recurrent NOTCH2 mutations and, more generally, mutually exclusive lesions affecting signalling pathways involved in normal MZ differentiation (Kiel et al, 2012;Rossi et al, 2012;Parry et al, 2013;Mart ınez et al, 2014). Otherwise, if CBL-MZ represent the early phase of a SLLU, they might harbour MAP2K1 mutations and lack lesions of MZ differentiation genes (Waterfall et al, 2014).To unravel the genetics of CBL-MZ, mutations of the NOTCH2, NOTCH1, BIRC3, TNFAIP3, TRAF3, IKBKB, MYD88, CD79A, CD79B, CARD11, BRAF and MAP2K1 genes were investigated on peripheral blood (PB) samples (tumour representation >50%) from 16 CBL-MZ identified according to the criteria defined by Xochelli et al (2014), namely: (i) persistent monoclonal B-cell lymphocytosis in the PB; (ii) immnophenotypic features consistent with a MZ lymphoproliferation, including lack of CD5, CD10, and CD103 expression and a Matutes score <2; (iii) bone marrow (BM) infiltration by small lymphocytes with no or limited plasmacytic differentiation; (iv) absence of lymphadenopathy, splenomegaly or extranodal tissue organomegaly by computerized tomography scan. BM biopsies were reviewed by experienced haematopathologists. Patients provided informed consent in accordance with the Declaration of Helsinki. The study was approved by the Ethical Committee (Protocol Code CE 116/12).Median absolute lymphocyte count of CBL-MZ was 11Á4 9 10 9 /l (range: 4Á5-23Á9 9 10 9 /l) and the median tumour B-cell count was 8Á1 9 10 9 /l (range: 3Á4-19Á8 9 10 9 /l) ( Table SI). According to current diagnostic criteria, 43% (7/16) could be classified as non-CLL type of monoclonal B-cell lymphocytosis (Marti et al, 2005). A small (<10 g/l) serum monoclonal component of IgM type was detected in 25% of cases (95% confidence interval [CI]: 9-49%; n = 4/16). After a median follow-up of 44 months, 18% (95% CI: 5-...

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“…We were not able to assess LOH for these 2 cases. Recent work has identified truncating SPEN and NOTCH2 mutations in splenic marginal zone lymphoma (21). Of note, none of the SPEN mutations reported had evidence for loss of the wild-type allele, similarly arguing against a simple lossof-function mechanism for SPEN mutation in this cancer type.…”

Section: Resultsmentioning

confidence: 99%

Whole exome sequencing of adenoid cystic carcinoma

Stephens¹,

Davies²,

Mitani³

et al. 2013

J. Clin. Invest.

237

274

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Adenoid cystic carcinoma (ACC) is a rare malignancy that can occur in multiple organ sites and is primarily found in the salivary gland. While the identification of recurrent fusions of the MYB-NFIB genes have begun to shed light on the molecular underpinnings, little else is known about the molecular genetics of this frequently fatal cancer. We have undertaken exome sequencing in a series of 24 ACC to further delineate the genetics of the disease. We identified multiple mutated genes that, combined, implicate chromatin deregulation in half of cases. Further, mutations were identified in known cancer genes, including PIK3CA, ATM, CDKN2A, SF3B1, SUFU, TSC1, and CYLD. Mutations in NOTCH1/2 were identified in 3 cases, and we identify the negative NOTCH signaling regulator, SPEN, as a new cancer gene in ACC with mutations in 5 cases. Finally, the identification of 3 likely activating mutations in the tyrosine kinase receptor FGFR2, analogous to those reported in ovarian and endometrial carcinoma, point to potential therapeutic avenues for a subset of cases.

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The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development

Abstract: Notch2 mutations represent the most frequent lesion in splenic marginal zone lymphoma.

Cited by 350 publications

References 62 publications

Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

Molecular lesions of signalling pathway genes in clonal B‐cell lymphocytosis with marginal zone features

Whole exome sequencing of adenoid cystic carcinoma

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