Gene Mutation Profiles in Primary Diffuse Large B Cell Lymphoma of Central Nervous System: Next Generation Sequencing Analyses

doi:10.3390/ijms17050683

. 2016 May 6;17(5):683.

doi: 10.3390/ijms17050683.

Gene Mutation Profiles in Primary Diffuse Large B Cell Lymphoma of Central Nervous System: Next Generation Sequencing Analyses

Milena Todorovic Balint^{1

2}, Jelena Jelicic³, Biljana Mihaljevic^{4

5}, Jelena Kostic⁶, Bojana Stanic⁷, Bela Balint⁸, Nadja Pejanovic⁹, Bojana Lucic¹⁰, Natasa Tosic¹¹, Irena Marjanovic¹², Maja Stojiljkovic¹³, Teodora Karan-Djurasevic¹⁴, Ognjen Perisic¹⁵, Goran Rakocevic¹⁶, Milos Popovic¹⁷, Sava Raicevic¹⁸, Jelena Bila^{19

20}, Darko Antic^{21

22}, Bosko Andjelic^{23

24}, Sonja Pavlovic²⁵

Affiliations

¹ Clinic for Hematology, Clinical Center of Serbia, Belgrade 11000, Serbia. bb.lena@gmail.com.
² Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia. bb.lena@gmail.com.
³ Clinic for Hematology, Clinical Center of Serbia, Belgrade 11000, Serbia. jecajelicic@yahoo.com.
⁴ Clinic for Hematology, Clinical Center of Serbia, Belgrade 11000, Serbia. zmzg@sezampro.rs.
⁵ Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia. zmzg@sezampro.rs.
⁶ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11010, Serbia. kostichelena@gmail.com.
⁷ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11010, Serbia. bojanastanic@yahoo.com.
⁸ Institute of Transfusiology and Hemobiology of Military Medical Academy, Belgrade 11000, Serbia. belabalint26@yahoo.com.
⁹ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11010, Serbia. nadjapejanovic@gmail.com.
¹⁰ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11010, Serbia. lucic.bojana@gmail.com.
¹¹ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11010, Serbia. nmtosic@sezampro.rs.
¹² Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11010, Serbia. irenas24@gmail.com.
¹³ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11010, Serbia. maja.stojiljkovic@yahoo.com.
¹⁴ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11010, Serbia. dora_karan@yahoo.com.
¹⁵ Seven Bridges Genomics, Belgrade 11000, Serbia. ognjen.perisic@gmail.com.
¹⁶ Seven Bridges Genomics, Belgrade 11000, Serbia. goran.rakocevic@sbgenomics.com.
¹⁷ Seven Bridges Genomics, Belgrade 11000, Serbia. milos.popovic@sbgenomics.com.
¹⁸ Department of Histopathology, Clinical Center of Serbia, Belgrade 11000, Serbia. jjelicic86@gmail.com.
¹⁹ Clinic for Hematology, Clinical Center of Serbia, Belgrade 11000, Serbia. idabakrac123@gmail.com.
²⁰ Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia. idabakrac123@gmail.com.
²¹ Clinic for Hematology, Clinical Center of Serbia, Belgrade 11000, Serbia. milosmak13@gmail.com.
²² Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia. milosmak13@gmail.com.
²³ Clinic for Hematology, Clinical Center of Serbia, Belgrade 11000, Serbia. belab@imi.bg.ac.rs.
²⁴ Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia. belab@imi.bg.ac.rs.
²⁵ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11010, Serbia. sonya@sezampro.rs.

PMID: 27164089
PMCID: PMC4881509
DOI: 10.3390/ijms17050683

Gene Mutation Profiles in Primary Diffuse Large B Cell Lymphoma of Central Nervous System: Next Generation Sequencing Analyses

Milena Todorovic Balint et al. Int J Mol Sci. 2016.

. 2016 May 6;17(5):683.

doi: 10.3390/ijms17050683.

Authors

Affiliations

¹ Clinic for Hematology, Clinical Center of Serbia, Belgrade 11000, Serbia. bb.lena@gmail.com.
² Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia. bb.lena@gmail.com.
³ Clinic for Hematology, Clinical Center of Serbia, Belgrade 11000, Serbia. jecajelicic@yahoo.com.
⁴ Clinic for Hematology, Clinical Center of Serbia, Belgrade 11000, Serbia. zmzg@sezampro.rs.
⁵ Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia. zmzg@sezampro.rs.
⁶ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11010, Serbia. kostichelena@gmail.com.
⁷ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11010, Serbia. bojanastanic@yahoo.com.
⁸ Institute of Transfusiology and Hemobiology of Military Medical Academy, Belgrade 11000, Serbia. belabalint26@yahoo.com.
⁹ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11010, Serbia. nadjapejanovic@gmail.com.
¹⁰ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11010, Serbia. lucic.bojana@gmail.com.
¹¹ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11010, Serbia. nmtosic@sezampro.rs.
¹² Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11010, Serbia. irenas24@gmail.com.
¹³ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11010, Serbia. maja.stojiljkovic@yahoo.com.
¹⁴ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11010, Serbia. dora_karan@yahoo.com.
¹⁵ Seven Bridges Genomics, Belgrade 11000, Serbia. ognjen.perisic@gmail.com.
¹⁶ Seven Bridges Genomics, Belgrade 11000, Serbia. goran.rakocevic@sbgenomics.com.
¹⁷ Seven Bridges Genomics, Belgrade 11000, Serbia. milos.popovic@sbgenomics.com.
¹⁸ Department of Histopathology, Clinical Center of Serbia, Belgrade 11000, Serbia. jjelicic86@gmail.com.
¹⁹ Clinic for Hematology, Clinical Center of Serbia, Belgrade 11000, Serbia. idabakrac123@gmail.com.
²⁰ Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia. idabakrac123@gmail.com.
²¹ Clinic for Hematology, Clinical Center of Serbia, Belgrade 11000, Serbia. milosmak13@gmail.com.
²² Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia. milosmak13@gmail.com.
²³ Clinic for Hematology, Clinical Center of Serbia, Belgrade 11000, Serbia. belab@imi.bg.ac.rs.
²⁴ Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia. belab@imi.bg.ac.rs.
²⁵ Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11010, Serbia. sonya@sezampro.rs.

PMID: 27164089
PMCID: PMC4881509
DOI: 10.3390/ijms17050683

Abstract

The existence of a potential primary central nervous system lymphoma-specific genomic signature that differs from the systemic form of diffuse large B cell lymphoma (DLBCL) has been suggested, but is still controversial. We investigated 19 patients with primary DLBCL of central nervous system (DLBCL CNS) using the TruSeq Amplicon Cancer Panel (TSACP) for 48 cancer-related genes. Next generation sequencing (NGS) analyses have revealed that over 80% of potentially protein-changing mutations were located in eight genes (CTNNB1, PIK3CA, PTEN, ATM, KRAS, PTPN11, TP53 and JAK3), pointing to the potential role of these genes in lymphomagenesis. TP53 was the only gene harboring mutations in all 19 patients. In addition, the presence of mutated TP53 and ATM genes correlated with a higher total number of mutations in other analyzed genes. Furthermore, the presence of mutated ATM correlated with poorer event-free survival (EFS) (p = 0.036). The presence of the mutated SMO gene correlated with earlier disease relapse (p = 0.023), inferior event-free survival (p = 0.011) and overall survival (OS) (p = 0.017), while mutations in the PTEN gene were associated with inferior OS (p = 0.048). Our findings suggest that the TP53 and ATM genes could be involved in the molecular pathophysiology of primary DLBCL CNS, whereas mutations in the PTEN and SMO genes could affect survival regardless of the initial treatment approach.

Keywords: ATM; PTEN; SMO; TP53; primary DLBCL CNS.

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Figures

**Figure 1**
The number of mutations per primary DLBCL CNS patient. (A) Total number of mutations in coding and non-coding regions identified by targeted NGS; (B) distribution of nonsense (N), frameshift (F) and missense (M) mutations in coding regions of targeted genes.

**Figure 2**
The number of mutations per targeted gene. Distribution of NFM mutations in the coding regions of targeted genes.

**Figure 3**
OncoPrint showing the distribution of genetic alterations in 40 targeted tumor suppressor and oncogenes in 19 primary DLBCL CNS patients. The type of mutations are labeled in the color legend, particular genes in rows and tumor samples in columns.

**Figure 4**
Overall survival according to the presence of NFM mutations in the *PTEN* gene (A) and the *SMO* gene (B).

See this image and copyright information in PMC

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References

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1. Montesinos-Rongen M., Schmitz R., Brunn A., Gesk S., Richter J., Hong K., Wiestler O.D., Siebert R., Kuppers R., Deckert M. Mutations of CARD11 but not TNFAIP3 may activate the NF-κB pathway in primary CNS lymphoma. Acta Neuropathol. 2010;120:529–535. doi: 10.1007/s00401-010-0709-7. - DOI - PubMed
1. Ponzoni M., Issa S., Batchelor T.T., Rubenstein J.L. Beyond high-dose methotrexate and brain radiotherapy: Novel targets and agents for primary CNS lymphoma. Ann. Oncol. 2014;25:316–322. doi: 10.1093/annonc/mdt385. - DOI - PMC - PubMed
1. Sung C.O., Kim S.C., Karnan S., Karube K., Shin H.J., Nam D.H., Suh Y.L., Kim S.H., Kim J.Y., Kim S.J., Kim W.S., et al. Genomic profiling combined with gene expression profiling in primary central nervous system lymphoma. Blood. 2011;117:1291–1300. doi: 10.1182/blood-2010-07-297861. - DOI - PubMed
1. Tun H.W., Personett D., Baskerville K.A., Menke D.M., Jaeckle K.A., Kreinest P., Edenfield B., Zubair A.C., O’Neill B.P., Lai W.R., et al. Pathway analysis of primary central nervous system lymphoma. Blood. 2008;111:3200–3210. doi: 10.1182/blood-2007-10-119099. - DOI - PMC - PubMed

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[1] Hoang-Xuan K., Bessell E., Bromberg J., Hottinger A.F., Preusser M., Ruda R., Schlegel U., Siegal T., Soussain C., Abacioglu U., et al. Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: Guidelines from the European Association for Neuro-Oncology. Lancet Oncol. 2015;16:e322–e332. doi: 10.1016/S1470-2045(15)00076-5. - DOI - PubMed

[2] Hoang-Xuan K., Bessell E., Bromberg J., Hottinger A.F., Preusser M., Ruda R., Schlegel U., Siegal T., Soussain C., Abacioglu U., et al. Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: Guidelines from the European Association for Neuro-Oncology. Lancet Oncol. 2015;16:e322–e332. doi: 10.1016/S1470-2045(15)00076-5. - DOI - PubMed

[3] Montesinos-Rongen M., Schmitz R., Brunn A., Gesk S., Richter J., Hong K., Wiestler O.D., Siebert R., Kuppers R., Deckert M. Mutations of CARD11 but not TNFAIP3 may activate the NF-κB pathway in primary CNS lymphoma. Acta Neuropathol. 2010;120:529–535. doi: 10.1007/s00401-010-0709-7. - DOI - PubMed

[4] Montesinos-Rongen M., Schmitz R., Brunn A., Gesk S., Richter J., Hong K., Wiestler O.D., Siebert R., Kuppers R., Deckert M. Mutations of CARD11 but not TNFAIP3 may activate the NF-κB pathway in primary CNS lymphoma. Acta Neuropathol. 2010;120:529–535. doi: 10.1007/s00401-010-0709-7. - DOI - PubMed

[5] Ponzoni M., Issa S., Batchelor T.T., Rubenstein J.L. Beyond high-dose methotrexate and brain radiotherapy: Novel targets and agents for primary CNS lymphoma. Ann. Oncol. 2014;25:316–322. doi: 10.1093/annonc/mdt385. - DOI - PMC - PubMed

[6] Ponzoni M., Issa S., Batchelor T.T., Rubenstein J.L. Beyond high-dose methotrexate and brain radiotherapy: Novel targets and agents for primary CNS lymphoma. Ann. Oncol. 2014;25:316–322. doi: 10.1093/annonc/mdt385. - DOI - PMC - PubMed

[7] Sung C.O., Kim S.C., Karnan S., Karube K., Shin H.J., Nam D.H., Suh Y.L., Kim S.H., Kim J.Y., Kim S.J., Kim W.S., et al. Genomic profiling combined with gene expression profiling in primary central nervous system lymphoma. Blood. 2011;117:1291–1300. doi: 10.1182/blood-2010-07-297861. - DOI - PubMed

[8] Sung C.O., Kim S.C., Karnan S., Karube K., Shin H.J., Nam D.H., Suh Y.L., Kim S.H., Kim J.Y., Kim S.J., Kim W.S., et al. Genomic profiling combined with gene expression profiling in primary central nervous system lymphoma. Blood. 2011;117:1291–1300. doi: 10.1182/blood-2010-07-297861. - DOI - PubMed

[9] Tun H.W., Personett D., Baskerville K.A., Menke D.M., Jaeckle K.A., Kreinest P., Edenfield B., Zubair A.C., O’Neill B.P., Lai W.R., et al. Pathway analysis of primary central nervous system lymphoma. Blood. 2008;111:3200–3210. doi: 10.1182/blood-2007-10-119099. - DOI - PMC - PubMed

[10] Tun H.W., Personett D., Baskerville K.A., Menke D.M., Jaeckle K.A., Kreinest P., Edenfield B., Zubair A.C., O’Neill B.P., Lai W.R., et al. Pathway analysis of primary central nervous system lymphoma. Blood. 2008;111:3200–3210. doi: 10.1182/blood-2007-10-119099. - DOI - PMC - PubMed

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Gene Mutation Profiles in Primary Diffuse Large B Cell Lymphoma of Central Nervous System: Next Generation Sequencing Analyses

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Gene Mutation Profiles in Primary Diffuse Large B Cell Lymphoma of Central Nervous System: Next Generation Sequencing Analyses

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