Nodal marginal zone lymphoma (NMZL) is a rare indolent B-cell tumor that is distinguished from splenic marginal zone lymphoma (SMZL) by the different pattern of dissemination. NMZL still lacks distinct markers and remains orphan of specific cancer gene lesions. By combining whole exome sequencing, targeted sequencing of tumor-related genes, whole transcriptome sequencing, and high resolution SNP array analysis, we aimed at disclosing the pathways that are molecularly deregulated in NMZL and compare the molecular profile of NMZL with that of SMZL. These analyses identified a distinctive pattern of non-silent somatic lesions in NMZL. In 35 NMZL patients, 41 genes were found recurrently affected in ≥3 (9%) of cases, including highly prevalent molecular lesions of MLL2 (also known as KMT2D; 34%), PTPRD (20%), NOTCH2 (20%), and KLF2 (17%). Mutations of PTPRD, a receptor-type protein tyrosine phosphatase regulating cell growth, were enriched in NMZL across mature B-cell tumors, functionally caused the loss of the phosphatase activity of PTPRD, and associated with cell cycle transcriptional program deregulation and increased proliferation index in NMZL. Though NMZL shared with SMZL a common mutation profile, NMZL harbored PTPRD lesions that were otherwise absent in SMZL. Collectively, these findings provide new insights into the genetics of NMZL, identify PTPRD lesions as a novel marker for this lymphoma across mature B-cell tumors, and support the distinction of NMZL as an independent clinico-pathologic entity within the current lymphoma classification.
The genetics of nodal marginal zone lymphoma / Spina, Valeria; Khiabanian, Hossein; Messina, Monica; Monti, Sara; Cascione, Luciano; Bruscaggin, Alessio; Spaccarotella, Elisa; Holmes, Antony B; Arcaini, Luca; Lucioni, Marco; Tabbò, Fabrizio; Zairis, Sakellarios; Diop, Fary; Cerri, Michaela; Chiaretti, Sabina; Marasca, Roberto; Ponzoni, Maurilio; Deaglio, Silvia; Ramponi, Antonio; Tiacci, Enrico; Pasqualucci, Laura; Paulli, Marco; Falini, Brunangelo; Inghirami, Giorgio; Bertoni, Francesco; Foa, Roberto; Rabadan, Raul; Gaidano, Gianluca; Rossi, Davide. - In: BLOOD. - ISSN 0006-4971. - (2016). [10.1182/blood-2016-02-696757]
The genetics of nodal marginal zone lymphoma
MESSINA, MONICA;CHIARETTI, sabina;FOA, Roberto;
2016
Abstract
Nodal marginal zone lymphoma (NMZL) is a rare indolent B-cell tumor that is distinguished from splenic marginal zone lymphoma (SMZL) by the different pattern of dissemination. NMZL still lacks distinct markers and remains orphan of specific cancer gene lesions. By combining whole exome sequencing, targeted sequencing of tumor-related genes, whole transcriptome sequencing, and high resolution SNP array analysis, we aimed at disclosing the pathways that are molecularly deregulated in NMZL and compare the molecular profile of NMZL with that of SMZL. These analyses identified a distinctive pattern of non-silent somatic lesions in NMZL. In 35 NMZL patients, 41 genes were found recurrently affected in ≥3 (9%) of cases, including highly prevalent molecular lesions of MLL2 (also known as KMT2D; 34%), PTPRD (20%), NOTCH2 (20%), and KLF2 (17%). Mutations of PTPRD, a receptor-type protein tyrosine phosphatase regulating cell growth, were enriched in NMZL across mature B-cell tumors, functionally caused the loss of the phosphatase activity of PTPRD, and associated with cell cycle transcriptional program deregulation and increased proliferation index in NMZL. Though NMZL shared with SMZL a common mutation profile, NMZL harbored PTPRD lesions that were otherwise absent in SMZL. Collectively, these findings provide new insights into the genetics of NMZL, identify PTPRD lesions as a novel marker for this lymphoma across mature B-cell tumors, and support the distinction of NMZL as an independent clinico-pathologic entity within the current lymphoma classification.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
