Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma

Bruno M. Grande, Daniela S. Gerhard, Aixiang Jiang, Nicholas B. Griner, Jeremy S. Abramson, Thomas B. Alexander, Hilary Allen, Leona W. Ayers, Jeffrey M. Bethony, Kishor Bhatia, Jay Bowen, Corey Casper, John Kim Choi, Luka Culibrk, Tanja M. Davidsen, Maureen A. Dyer, Julie M. Gastier-Foster, Patee Gesuwan, Timothy C. Greiner, Thomas G. Gross & 33 others Benjamin Hanf, Nancy Lee Harris, Yiwen He, John D. Irvin, Elaine S. Jaffe, Steven J.M. Jones, Patrick Kerchan, Nicole Knoetze, Fabio E. Leal, Tara M. Lichtenberg, Yussanne Ma, Jean Paul Martin, Marie Reine Martin, Sam M. Mbulaiteye, Charles G. Mullighan, Andrew J. Mungall, Constance Namirembe, Karen Novik, Ariela Noy, Martin D. Ogwang, Abraham Omoding, Jackson Orem, Steven James Reynolds, Christopher K. Rushton, John T. Sandlund, Roland Schmitz, Cynthia Taylor, Wyndham H. Wilson, George W. Wright, Eric Y. Zhao, Marco A. Marra, Ryan D. Morin, Louis M. Staudt

Research output: Contribution to journalArticle

Abstract

Although generally curable with intensive chemotherapy in resource-rich settings, Burkitt lymphoma (BL) remains a deadly disease in older patients and in sub-Saharan Africa. Epstein-Barr virus (EBV) positivity is a feature in more than 90% of cases in malaria-endemic regions, and up to 30% elsewhere. However, the molecular features of BL have not been comprehensively evaluated when taking into account tumor EBV status or geographic origin. Through an integrative analysis of whole-genome and transcriptome data, we show a striking genome-wide increase in aberrant somatic hypermutation in EBV-positive tumors, supporting a link between EBV and activation-induced cytidine deaminase (AICDA) activity. In addition to identifying novel candidate BL genes such as SIN3A, USP7, and CHD8, we demonstrate that EBV-positive tumors had significantly fewer driver mutations, especially among genes with roles in apoptosis. We also found immunoglobulin variable region genes that were disproportionally used to encode clonal B-cell receptors (BCRs) in the tumors. These include IGHV4-34, known to produce autoreactive antibodies, and IGKV3-20, a feature described in other B-cell malignancies but not yet in BL. Our results suggest that tumor EBV status defines a specific BL phenotype irrespective of geographic origin, with particular molecular properties and distinct pathogenic mechanisms. The novel mutation patterns identified here imply rational use of DNA-damaging chemotherapy in some patients with BL and targeted agents such as the CDK4/6 inhibitor palbociclib in others, whereas the importance of BCR signaling in BL strengthens the potential benefit of inhibitors for PI3K, Syk, and Src family kinases among these patients.

Original languageEnglish (US)
Pages (from-to)1313-1324
Number of pages12
JournalBlood
Volume133
Issue number12
DOIs
StatePublished - Mar 21 2019
Externally publishedYes

Fingerprint

Pediatrics
Burkitt Lymphoma
Viruses
Human Herpesvirus 4
Genes
Tumors
Genome
Mutation
Chemotherapy
Oncogenic Viruses
B-Lymphocytes
Cells
Neoplasms
Immunoglobulin Variable Region
src-Family Kinases
Virus Activation
Drug Therapy
Phosphatidylinositol 3-Kinases
Africa South of the Sahara
Transcriptome

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Grande, B. M., Gerhard, D. S., Jiang, A., Griner, N. B., Abramson, J. S., Alexander, T. B., ... Staudt, L. M. (2019). Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma. Blood, 133(12), 1313-1324. https://doi.org/10.1182/blood-2018-09-871418

Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma. / Grande, Bruno M.; Gerhard, Daniela S.; Jiang, Aixiang; Griner, Nicholas B.; Abramson, Jeremy S.; Alexander, Thomas B.; Allen, Hilary; Ayers, Leona W.; Bethony, Jeffrey M.; Bhatia, Kishor; Bowen, Jay; Casper, Corey; Choi, John Kim; Culibrk, Luka; Davidsen, Tanja M.; Dyer, Maureen A.; Gastier-Foster, Julie M.; Gesuwan, Patee; Greiner, Timothy C.; Gross, Thomas G.; Hanf, Benjamin; Harris, Nancy Lee; He, Yiwen; Irvin, John D.; Jaffe, Elaine S.; Jones, Steven J.M.; Kerchan, Patrick; Knoetze, Nicole; Leal, Fabio E.; Lichtenberg, Tara M.; Ma, Yussanne; Martin, Jean Paul; Martin, Marie Reine; Mbulaiteye, Sam M.; Mullighan, Charles G.; Mungall, Andrew J.; Namirembe, Constance; Novik, Karen; Noy, Ariela; Ogwang, Martin D.; Omoding, Abraham; Orem, Jackson; Reynolds, Steven James; Rushton, Christopher K.; Sandlund, John T.; Schmitz, Roland; Taylor, Cynthia; Wilson, Wyndham H.; Wright, George W.; Zhao, Eric Y.; Marra, Marco A.; Morin, Ryan D.; Staudt, Louis M.

In: Blood, Vol. 133, No. 12, 21.03.2019, p. 1313-1324.

Research output: Contribution to journalArticle

Grande, BM, Gerhard, DS, Jiang, A, Griner, NB, Abramson, JS, Alexander, TB, Allen, H, Ayers, LW, Bethony, JM, Bhatia, K, Bowen, J, Casper, C, Choi, JK, Culibrk, L, Davidsen, TM, Dyer, MA, Gastier-Foster, JM, Gesuwan, P, Greiner, TC, Gross, TG, Hanf, B, Harris, NL, He, Y, Irvin, JD, Jaffe, ES, Jones, SJM, Kerchan, P, Knoetze, N, Leal, FE, Lichtenberg, TM, Ma, Y, Martin, JP, Martin, MR, Mbulaiteye, SM, Mullighan, CG, Mungall, AJ, Namirembe, C, Novik, K, Noy, A, Ogwang, MD, Omoding, A, Orem, J, Reynolds, SJ, Rushton, CK, Sandlund, JT, Schmitz, R, Taylor, C, Wilson, WH, Wright, GW, Zhao, EY, Marra, MA, Morin, RD & Staudt, LM 2019, 'Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma', Blood, vol. 133, no. 12, pp. 1313-1324. https://doi.org/10.1182/blood-2018-09-871418
Grande BM, Gerhard DS, Jiang A, Griner NB, Abramson JS, Alexander TB et al. Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma. Blood. 2019 Mar 21;133(12):1313-1324. https://doi.org/10.1182/blood-2018-09-871418
Grande, Bruno M. ; Gerhard, Daniela S. ; Jiang, Aixiang ; Griner, Nicholas B. ; Abramson, Jeremy S. ; Alexander, Thomas B. ; Allen, Hilary ; Ayers, Leona W. ; Bethony, Jeffrey M. ; Bhatia, Kishor ; Bowen, Jay ; Casper, Corey ; Choi, John Kim ; Culibrk, Luka ; Davidsen, Tanja M. ; Dyer, Maureen A. ; Gastier-Foster, Julie M. ; Gesuwan, Patee ; Greiner, Timothy C. ; Gross, Thomas G. ; Hanf, Benjamin ; Harris, Nancy Lee ; He, Yiwen ; Irvin, John D. ; Jaffe, Elaine S. ; Jones, Steven J.M. ; Kerchan, Patrick ; Knoetze, Nicole ; Leal, Fabio E. ; Lichtenberg, Tara M. ; Ma, Yussanne ; Martin, Jean Paul ; Martin, Marie Reine ; Mbulaiteye, Sam M. ; Mullighan, Charles G. ; Mungall, Andrew J. ; Namirembe, Constance ; Novik, Karen ; Noy, Ariela ; Ogwang, Martin D. ; Omoding, Abraham ; Orem, Jackson ; Reynolds, Steven James ; Rushton, Christopher K. ; Sandlund, John T. ; Schmitz, Roland ; Taylor, Cynthia ; Wilson, Wyndham H. ; Wright, George W. ; Zhao, Eric Y. ; Marra, Marco A. ; Morin, Ryan D. ; Staudt, Louis M. / Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma. In: Blood. 2019 ; Vol. 133, No. 12. pp. 1313-1324.
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abstract = "Although generally curable with intensive chemotherapy in resource-rich settings, Burkitt lymphoma (BL) remains a deadly disease in older patients and in sub-Saharan Africa. Epstein-Barr virus (EBV) positivity is a feature in more than 90{\%} of cases in malaria-endemic regions, and up to 30{\%} elsewhere. However, the molecular features of BL have not been comprehensively evaluated when taking into account tumor EBV status or geographic origin. Through an integrative analysis of whole-genome and transcriptome data, we show a striking genome-wide increase in aberrant somatic hypermutation in EBV-positive tumors, supporting a link between EBV and activation-induced cytidine deaminase (AICDA) activity. In addition to identifying novel candidate BL genes such as SIN3A, USP7, and CHD8, we demonstrate that EBV-positive tumors had significantly fewer driver mutations, especially among genes with roles in apoptosis. We also found immunoglobulin variable region genes that were disproportionally used to encode clonal B-cell receptors (BCRs) in the tumors. These include IGHV4-34, known to produce autoreactive antibodies, and IGKV3-20, a feature described in other B-cell malignancies but not yet in BL. Our results suggest that tumor EBV status defines a specific BL phenotype irrespective of geographic origin, with particular molecular properties and distinct pathogenic mechanisms. The novel mutation patterns identified here imply rational use of DNA-damaging chemotherapy in some patients with BL and targeted agents such as the CDK4/6 inhibitor palbociclib in others, whereas the importance of BCR signaling in BL strengthens the potential benefit of inhibitors for PI3K, Syk, and Src family kinases among these patients.",
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T1 - Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma

AU - Grande, Bruno M.

AU - Gerhard, Daniela S.

AU - Jiang, Aixiang

AU - Griner, Nicholas B.

AU - Abramson, Jeremy S.

AU - Alexander, Thomas B.

AU - Allen, Hilary

AU - Ayers, Leona W.

AU - Bethony, Jeffrey M.

AU - Bhatia, Kishor

AU - Bowen, Jay

AU - Casper, Corey

AU - Choi, John Kim

AU - Culibrk, Luka

AU - Davidsen, Tanja M.

AU - Dyer, Maureen A.

AU - Gastier-Foster, Julie M.

AU - Gesuwan, Patee

AU - Greiner, Timothy C.

AU - Gross, Thomas G.

AU - Hanf, Benjamin

AU - Harris, Nancy Lee

AU - He, Yiwen

AU - Irvin, John D.

AU - Jaffe, Elaine S.

AU - Jones, Steven J.M.

AU - Kerchan, Patrick

AU - Knoetze, Nicole

AU - Leal, Fabio E.

AU - Lichtenberg, Tara M.

AU - Ma, Yussanne

AU - Martin, Jean Paul

AU - Martin, Marie Reine

AU - Mbulaiteye, Sam M.

AU - Mullighan, Charles G.

AU - Mungall, Andrew J.

AU - Namirembe, Constance

AU - Novik, Karen

AU - Noy, Ariela

AU - Ogwang, Martin D.

AU - Omoding, Abraham

AU - Orem, Jackson

AU - Reynolds, Steven James

AU - Rushton, Christopher K.

AU - Sandlund, John T.

AU - Schmitz, Roland

AU - Taylor, Cynthia

AU - Wilson, Wyndham H.

AU - Wright, George W.

AU - Zhao, Eric Y.

AU - Marra, Marco A.

AU - Morin, Ryan D.

AU - Staudt, Louis M.

PY - 2019/3/21

Y1 - 2019/3/21

N2 - Although generally curable with intensive chemotherapy in resource-rich settings, Burkitt lymphoma (BL) remains a deadly disease in older patients and in sub-Saharan Africa. Epstein-Barr virus (EBV) positivity is a feature in more than 90% of cases in malaria-endemic regions, and up to 30% elsewhere. However, the molecular features of BL have not been comprehensively evaluated when taking into account tumor EBV status or geographic origin. Through an integrative analysis of whole-genome and transcriptome data, we show a striking genome-wide increase in aberrant somatic hypermutation in EBV-positive tumors, supporting a link between EBV and activation-induced cytidine deaminase (AICDA) activity. In addition to identifying novel candidate BL genes such as SIN3A, USP7, and CHD8, we demonstrate that EBV-positive tumors had significantly fewer driver mutations, especially among genes with roles in apoptosis. We also found immunoglobulin variable region genes that were disproportionally used to encode clonal B-cell receptors (BCRs) in the tumors. These include IGHV4-34, known to produce autoreactive antibodies, and IGKV3-20, a feature described in other B-cell malignancies but not yet in BL. Our results suggest that tumor EBV status defines a specific BL phenotype irrespective of geographic origin, with particular molecular properties and distinct pathogenic mechanisms. The novel mutation patterns identified here imply rational use of DNA-damaging chemotherapy in some patients with BL and targeted agents such as the CDK4/6 inhibitor palbociclib in others, whereas the importance of BCR signaling in BL strengthens the potential benefit of inhibitors for PI3K, Syk, and Src family kinases among these patients.

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