The genetics of nodal marginal zone lymphoma

Valeria Spina, Hossein Khiabanian, Monica Messina, Sara Monti, Luciano Cascione, Alessio Bruscaggin, Elisa Spaccarotella, Antony B. Holmes, Luca Arcaini, Marco Lucioni, Fabrizio Tabbò, Sakellarios Zairis, Fary Diop, Michaela Cerri, Sabina Chiaretti, Roberto Marasca, Maurilio Ponzoni, Silvia Deaglio, Antonio Ramponi, Enrico Tiacci & 9 others Laura Pasqualucci, Marco Paulli, Brunangelo Falini, Giorgio Inghirami, Francesco Bertoni, Robin Foà, Raul Rabadan, Gianluca Gaidano, Davide Rossi

Research output: Contribution to journalArticle

40 Citations (Scopus)

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 single nucleotide polymorphism array analysis, we aimed at disclosing the pathways that are molecularly deregulated in NMZL and we compare the molecular profile of NMZL with that of SMZL. These analyses identified a distinctive pattern of nonsilent somatic lesions in NMZL. In 35 NMZL patients, 41 genes were found recurrently affected in ≥3 (9%) 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 were associated with cell-cycle transcriptional program deregulation and increased proliferation index in NMZL. Although 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 clinicopathologic entity within the current lymphoma classification.

Original languageEnglish
Pages (from-to)1362-1373
Number of pages12
JournalBlood
Volume128
Issue number10
DOIs
Publication statusPublished - 2016

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Tumors
Lymphoma
Cells
Genes
Protein Tyrosine Phosphatases
Deregulation
Cell growth
Polymorphism
Phosphoric Monoester Hydrolases
Nucleotides
Genetics
B-Lymphocytes
Neoplasms
Exome
Mutation
Orphaned Children
Neoplasm Genes
Transcriptome
Single Nucleotide Polymorphism
Cell Cycle

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Spina, V., Khiabanian, H., Messina, M., Monti, S., Cascione, L., Bruscaggin, A., ... Rossi, D. (2016). The genetics of nodal marginal zone lymphoma. Blood, 128(10), 1362-1373. https://doi.org/10.1182/blood-2016-02-696757

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; Foà, Robin; Rabadan, Raul; Gaidano, Gianluca; Rossi, Davide.

In: Blood, Vol. 128, No. 10, 2016, p. 1362-1373.

Research output: Contribution to journalArticle

Spina, V, Khiabanian, H, Messina, M, Monti, S, Cascione, L, Bruscaggin, A, Spaccarotella, E, Holmes, AB, Arcaini, L, Lucioni, M, Tabbò, F, Zairis, S, Diop, F, Cerri, M, Chiaretti, S, Marasca, R, Ponzoni, M, Deaglio, S, Ramponi, A, Tiacci, E, Pasqualucci, L, Paulli, M, Falini, B, Inghirami, G, Bertoni, F, Foà, R, Rabadan, R, Gaidano, G & Rossi, D 2016, 'The genetics of nodal marginal zone lymphoma', Blood, vol. 128, no. 10, pp. 1362-1373. https://doi.org/10.1182/blood-2016-02-696757
Spina V, Khiabanian H, Messina M, Monti S, Cascione L, Bruscaggin A et al. The genetics of nodal marginal zone lymphoma. Blood. 2016;128(10):1362-1373. https://doi.org/10.1182/blood-2016-02-696757
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 ; Foà, Robin ; Rabadan, Raul ; Gaidano, Gianluca ; Rossi, Davide. / The genetics of nodal marginal zone lymphoma. In: Blood. 2016 ; Vol. 128, No. 10. pp. 1362-1373.
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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 single nucleotide polymorphism array analysis, we aimed at disclosing the pathways that are molecularly deregulated in NMZL and we compare the molecular profile of NMZL with that of SMZL. These analyses identified a distinctive pattern of nonsilent somatic lesions in NMZL. In 35 NMZL patients, 41 genes were found recurrently affected in ≥3 (9{\%}) 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 were associated with cell-cycle transcriptional program deregulation and increased proliferation index in NMZL. Although 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 clinicopathologic entity within the current lymphoma classification.",
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AU - Spina, Valeria

AU - Khiabanian, Hossein

AU - Messina, Monica

AU - Monti, Sara

AU - Cascione, Luciano

AU - Bruscaggin, Alessio

AU - Spaccarotella, Elisa

AU - Holmes, Antony B.

AU - Arcaini, Luca

AU - Lucioni, Marco

AU - Tabbò, Fabrizio

AU - Zairis, Sakellarios

AU - Diop, Fary

AU - Cerri, Michaela

AU - Chiaretti, Sabina

AU - Marasca, Roberto

AU - Ponzoni, Maurilio

AU - Deaglio, Silvia

AU - Ramponi, Antonio

AU - Tiacci, Enrico

AU - Pasqualucci, Laura

AU - Paulli, Marco

AU - Falini, Brunangelo

AU - Inghirami, Giorgio

AU - Bertoni, Francesco

AU - Foà, Robin

AU - Rabadan, Raul

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AU - Rossi, Davide

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N2 - 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 single nucleotide polymorphism array analysis, we aimed at disclosing the pathways that are molecularly deregulated in NMZL and we compare the molecular profile of NMZL with that of SMZL. These analyses identified a distinctive pattern of nonsilent somatic lesions in NMZL. In 35 NMZL patients, 41 genes were found recurrently affected in ≥3 (9%) 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 were associated with cell-cycle transcriptional program deregulation and increased proliferation index in NMZL. Although 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 clinicopathologic entity within the current lymphoma classification.

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