GENETIC LANDSCAPE OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
(Abstract release date: 05/19/16)
EHA Library. Yoshida K. 06/11/16; 135243; S487
Dr. Kenichi Yoshida
Contributions
Contributions
Abstract
Abstract: S487
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:00 - 16:15
Location: Auditorium 1
Background
Primary central nervous system lymphoma (PCNSL) is a rare subtype of non-Hodgkin lymphoma, of which approximately 95% are diffuse large B-cell lymphomas (DLBCLs). However, PCNSL shows very different biological and clinical characteristics from systemic DLBCL, and our knowledge about the molecular pathogenesis of PCNSL is still incomplete.
Aims
The purpose of this study is to delineate the entire spectrum of gene mutations, copy number alterations (CNAs) and structural variants (SVs) in PCNSL to better understand its pathogenesis.
Methods
We first analyzed paired tumor/normal DNA from 37 PCNSL cases by whole-exome sequencing (WES). Significantly mutated genes identified by WES and previously known mutational targets in PCNSL and systemic DLBCL were further screened for mutations using targeted sequencing in an extended cohort of PCNSL cases (N = 92). CNAs have been also investigated using SNP array-karyotyping (N =56). Whole-genome sequencing (WGS, N = 9) was also performed to identify the recurrent mutations in non-coding regions and SVs.
Results
The mean number of nonsynonymous mutations identified by WES was 183 per sample, which was comparable to the figure in systemic DLBCL. A higher representation of C>T transition involving CpG dinucleotides and hotspot mutations within the WRCY motif targeted by somatic hypermutations (SHMs) suggested the involvement of activation-induced cytidine deaminase (AID) in the pathogenesis of PCNSL. We found 12 genes significantly mutated in PCNSL (q < 0.1), including MYD88, PIM1, HLA-A, TMEM30A, B2M, PRDM1, UBE2A, HIST1H1C, GRB2 as well as several previously unreported mutational targets in systemic DLBCL or PCNSL, such as SETD1B, ITPKB, EIF4A2. Copy number analysis identified recurrent genomic segments affected by focal deletions (N = 27) and amplifications (N = 10), most of which included driver genes targeted by recurrent somatic mutations or known targets of focal CNAs such as CDKN2A and FHIT. Subsequent targeted sequencing finally identified a total of 107 significantly mutated genes, of which 43 were thought to be targeted by SHM according to their mutational signature. Most cases with PCNSL (98%) had mutations and CNAs involving genes that are relevant to constitutive NF-κB/Toll-like receptor (TLR)/B-cell receptor (BCR) activity, including those in MYD88, CD79B/A, CARD11, TNFAIP3, GRB2 and ITPKB. Genetic alterations implicated in escape from immunosurveillance were also frequently identified in as many as 76% of cases, including mutations of HLA-B, HLA-A, HLA-C, B2M and CD58 as well as CNAs in 6p21.32 (HLA class II), 1p13.1 (CD58) and 15q15.2 (B2M), suggesting the importance of immune escape in the pathogenesis of PCNSL. SHMs were observed in most cases (98%), which affected not only known non-immunoglobulin targets of AID including PIM1, IGLL5 and BTG2 but also previously unreported genes involved in cell proliferation, apoptosis, or B cell development. WGS identified 52 loci in which somatic mutations were enriched, including 5’-region of BCL6, RHOH, BACH2, genes known to undergo SHM. Furthermore, breakpoints clusters of SVs included IG loci (IGK, IGH and IGL), CDKN2A/B as well as known targets of AID, such as BCL6, BTG2 and PIM1.
Conclusion
Comprehensive genetic analyses of a large cohort of PCNSL cases revealed the genetic landscape of PCNSL, which was characterized by constitutive NF-κB/TLR/BCR signaling, escape from immunosurveillance, as well as SHMs/SVs caused by AID.
Session topic: Non-Hodgkin & Hodgkin lymphoma - Biology
Keyword(s): Diffuse large B cell lymphoma, Lymphoma
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:00 - 16:15
Location: Auditorium 1
Background
Primary central nervous system lymphoma (PCNSL) is a rare subtype of non-Hodgkin lymphoma, of which approximately 95% are diffuse large B-cell lymphomas (DLBCLs). However, PCNSL shows very different biological and clinical characteristics from systemic DLBCL, and our knowledge about the molecular pathogenesis of PCNSL is still incomplete.
Aims
The purpose of this study is to delineate the entire spectrum of gene mutations, copy number alterations (CNAs) and structural variants (SVs) in PCNSL to better understand its pathogenesis.
Methods
We first analyzed paired tumor/normal DNA from 37 PCNSL cases by whole-exome sequencing (WES). Significantly mutated genes identified by WES and previously known mutational targets in PCNSL and systemic DLBCL were further screened for mutations using targeted sequencing in an extended cohort of PCNSL cases (N = 92). CNAs have been also investigated using SNP array-karyotyping (N =56). Whole-genome sequencing (WGS, N = 9) was also performed to identify the recurrent mutations in non-coding regions and SVs.
Results
The mean number of nonsynonymous mutations identified by WES was 183 per sample, which was comparable to the figure in systemic DLBCL. A higher representation of C>T transition involving CpG dinucleotides and hotspot mutations within the WRCY motif targeted by somatic hypermutations (SHMs) suggested the involvement of activation-induced cytidine deaminase (AID) in the pathogenesis of PCNSL. We found 12 genes significantly mutated in PCNSL (q < 0.1), including MYD88, PIM1, HLA-A, TMEM30A, B2M, PRDM1, UBE2A, HIST1H1C, GRB2 as well as several previously unreported mutational targets in systemic DLBCL or PCNSL, such as SETD1B, ITPKB, EIF4A2. Copy number analysis identified recurrent genomic segments affected by focal deletions (N = 27) and amplifications (N = 10), most of which included driver genes targeted by recurrent somatic mutations or known targets of focal CNAs such as CDKN2A and FHIT. Subsequent targeted sequencing finally identified a total of 107 significantly mutated genes, of which 43 were thought to be targeted by SHM according to their mutational signature. Most cases with PCNSL (98%) had mutations and CNAs involving genes that are relevant to constitutive NF-κB/Toll-like receptor (TLR)/B-cell receptor (BCR) activity, including those in MYD88, CD79B/A, CARD11, TNFAIP3, GRB2 and ITPKB. Genetic alterations implicated in escape from immunosurveillance were also frequently identified in as many as 76% of cases, including mutations of HLA-B, HLA-A, HLA-C, B2M and CD58 as well as CNAs in 6p21.32 (HLA class II), 1p13.1 (CD58) and 15q15.2 (B2M), suggesting the importance of immune escape in the pathogenesis of PCNSL. SHMs were observed in most cases (98%), which affected not only known non-immunoglobulin targets of AID including PIM1, IGLL5 and BTG2 but also previously unreported genes involved in cell proliferation, apoptosis, or B cell development. WGS identified 52 loci in which somatic mutations were enriched, including 5’-region of BCL6, RHOH, BACH2, genes known to undergo SHM. Furthermore, breakpoints clusters of SVs included IG loci (IGK, IGH and IGL), CDKN2A/B as well as known targets of AID, such as BCL6, BTG2 and PIM1.
Conclusion
Comprehensive genetic analyses of a large cohort of PCNSL cases revealed the genetic landscape of PCNSL, which was characterized by constitutive NF-κB/TLR/BCR signaling, escape from immunosurveillance, as well as SHMs/SVs caused by AID.
Session topic: Non-Hodgkin & Hodgkin lymphoma - Biology
Keyword(s): Diffuse large B cell lymphoma, Lymphoma
Abstract: S487
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:00 - 16:15
Location: Auditorium 1
Background
Primary central nervous system lymphoma (PCNSL) is a rare subtype of non-Hodgkin lymphoma, of which approximately 95% are diffuse large B-cell lymphomas (DLBCLs). However, PCNSL shows very different biological and clinical characteristics from systemic DLBCL, and our knowledge about the molecular pathogenesis of PCNSL is still incomplete.
Aims
The purpose of this study is to delineate the entire spectrum of gene mutations, copy number alterations (CNAs) and structural variants (SVs) in PCNSL to better understand its pathogenesis.
Methods
We first analyzed paired tumor/normal DNA from 37 PCNSL cases by whole-exome sequencing (WES). Significantly mutated genes identified by WES and previously known mutational targets in PCNSL and systemic DLBCL were further screened for mutations using targeted sequencing in an extended cohort of PCNSL cases (N = 92). CNAs have been also investigated using SNP array-karyotyping (N =56). Whole-genome sequencing (WGS, N = 9) was also performed to identify the recurrent mutations in non-coding regions and SVs.
Results
The mean number of nonsynonymous mutations identified by WES was 183 per sample, which was comparable to the figure in systemic DLBCL. A higher representation of C>T transition involving CpG dinucleotides and hotspot mutations within the WRCY motif targeted by somatic hypermutations (SHMs) suggested the involvement of activation-induced cytidine deaminase (AID) in the pathogenesis of PCNSL. We found 12 genes significantly mutated in PCNSL (q < 0.1), including MYD88, PIM1, HLA-A, TMEM30A, B2M, PRDM1, UBE2A, HIST1H1C, GRB2 as well as several previously unreported mutational targets in systemic DLBCL or PCNSL, such as SETD1B, ITPKB, EIF4A2. Copy number analysis identified recurrent genomic segments affected by focal deletions (N = 27) and amplifications (N = 10), most of which included driver genes targeted by recurrent somatic mutations or known targets of focal CNAs such as CDKN2A and FHIT. Subsequent targeted sequencing finally identified a total of 107 significantly mutated genes, of which 43 were thought to be targeted by SHM according to their mutational signature. Most cases with PCNSL (98%) had mutations and CNAs involving genes that are relevant to constitutive NF-κB/Toll-like receptor (TLR)/B-cell receptor (BCR) activity, including those in MYD88, CD79B/A, CARD11, TNFAIP3, GRB2 and ITPKB. Genetic alterations implicated in escape from immunosurveillance were also frequently identified in as many as 76% of cases, including mutations of HLA-B, HLA-A, HLA-C, B2M and CD58 as well as CNAs in 6p21.32 (HLA class II), 1p13.1 (CD58) and 15q15.2 (B2M), suggesting the importance of immune escape in the pathogenesis of PCNSL. SHMs were observed in most cases (98%), which affected not only known non-immunoglobulin targets of AID including PIM1, IGLL5 and BTG2 but also previously unreported genes involved in cell proliferation, apoptosis, or B cell development. WGS identified 52 loci in which somatic mutations were enriched, including 5’-region of BCL6, RHOH, BACH2, genes known to undergo SHM. Furthermore, breakpoints clusters of SVs included IG loci (IGK, IGH and IGL), CDKN2A/B as well as known targets of AID, such as BCL6, BTG2 and PIM1.
Conclusion
Comprehensive genetic analyses of a large cohort of PCNSL cases revealed the genetic landscape of PCNSL, which was characterized by constitutive NF-κB/TLR/BCR signaling, escape from immunosurveillance, as well as SHMs/SVs caused by AID.
Session topic: Non-Hodgkin & Hodgkin lymphoma - Biology
Keyword(s): Diffuse large B cell lymphoma, Lymphoma
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:00 - 16:15
Location: Auditorium 1
Background
Primary central nervous system lymphoma (PCNSL) is a rare subtype of non-Hodgkin lymphoma, of which approximately 95% are diffuse large B-cell lymphomas (DLBCLs). However, PCNSL shows very different biological and clinical characteristics from systemic DLBCL, and our knowledge about the molecular pathogenesis of PCNSL is still incomplete.
Aims
The purpose of this study is to delineate the entire spectrum of gene mutations, copy number alterations (CNAs) and structural variants (SVs) in PCNSL to better understand its pathogenesis.
Methods
We first analyzed paired tumor/normal DNA from 37 PCNSL cases by whole-exome sequencing (WES). Significantly mutated genes identified by WES and previously known mutational targets in PCNSL and systemic DLBCL were further screened for mutations using targeted sequencing in an extended cohort of PCNSL cases (N = 92). CNAs have been also investigated using SNP array-karyotyping (N =56). Whole-genome sequencing (WGS, N = 9) was also performed to identify the recurrent mutations in non-coding regions and SVs.
Results
The mean number of nonsynonymous mutations identified by WES was 183 per sample, which was comparable to the figure in systemic DLBCL. A higher representation of C>T transition involving CpG dinucleotides and hotspot mutations within the WRCY motif targeted by somatic hypermutations (SHMs) suggested the involvement of activation-induced cytidine deaminase (AID) in the pathogenesis of PCNSL. We found 12 genes significantly mutated in PCNSL (q < 0.1), including MYD88, PIM1, HLA-A, TMEM30A, B2M, PRDM1, UBE2A, HIST1H1C, GRB2 as well as several previously unreported mutational targets in systemic DLBCL or PCNSL, such as SETD1B, ITPKB, EIF4A2. Copy number analysis identified recurrent genomic segments affected by focal deletions (N = 27) and amplifications (N = 10), most of which included driver genes targeted by recurrent somatic mutations or known targets of focal CNAs such as CDKN2A and FHIT. Subsequent targeted sequencing finally identified a total of 107 significantly mutated genes, of which 43 were thought to be targeted by SHM according to their mutational signature. Most cases with PCNSL (98%) had mutations and CNAs involving genes that are relevant to constitutive NF-κB/Toll-like receptor (TLR)/B-cell receptor (BCR) activity, including those in MYD88, CD79B/A, CARD11, TNFAIP3, GRB2 and ITPKB. Genetic alterations implicated in escape from immunosurveillance were also frequently identified in as many as 76% of cases, including mutations of HLA-B, HLA-A, HLA-C, B2M and CD58 as well as CNAs in 6p21.32 (HLA class II), 1p13.1 (CD58) and 15q15.2 (B2M), suggesting the importance of immune escape in the pathogenesis of PCNSL. SHMs were observed in most cases (98%), which affected not only known non-immunoglobulin targets of AID including PIM1, IGLL5 and BTG2 but also previously unreported genes involved in cell proliferation, apoptosis, or B cell development. WGS identified 52 loci in which somatic mutations were enriched, including 5’-region of BCL6, RHOH, BACH2, genes known to undergo SHM. Furthermore, breakpoints clusters of SVs included IG loci (IGK, IGH and IGL), CDKN2A/B as well as known targets of AID, such as BCL6, BTG2 and PIM1.
Conclusion
Comprehensive genetic analyses of a large cohort of PCNSL cases revealed the genetic landscape of PCNSL, which was characterized by constitutive NF-κB/TLR/BCR signaling, escape from immunosurveillance, as well as SHMs/SVs caused by AID.
Session topic: Non-Hodgkin & Hodgkin lymphoma - Biology
Keyword(s): Diffuse large B cell lymphoma, Lymphoma
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