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New research has revealed 5 genetic subtypes of diffuse large B-cell lymphoma (DLBCL).
Researchers identified a group of low-risk activated B-cell (ABC) DLBCLs, 2 subsets of germinal center B-cell (GCB) DLBCLs, a group of ABC/GCB-independent DLBCLs, and a group of ABC DLBCLs with genetic characteristics found in primary central nervous system lymphoma and testicular lymphoma.
The researchers believe these findings may have revealed new therapeutic targets for DLBCL, some of which could be inhibited by drugs that are already approved or under investigation in clinical trials.
Margaret Shipp, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and her colleagues conducted this research and reported the results in Nature Medicine.
The team performed genetic analyses on samples from 304 DLBCL patients and observed great genetic diversity. The median number of genetic driver alterations in individual tumors was 17.
The researchers integrated data on 3 types of genetic alterations—recurrent mutations, somatic copy number alterations, and structural variants—to define previously unappreciated DLBCL subtypes.
“Specific genes that were perturbed by mutations could also be altered by changes in gene copy numbers or by chromosomal rearrangements, underscoring the importance of evaluating all 3 types of genetic alterations,” Dr Shipp noted.
“Most importantly, we saw that there were 5 discrete types of DLBCL that were distinguished one from another on the basis of the specific types of genetic alterations that occurred in combination.”
The researchers classified these subtypes as clusters (C) 1 to 5.
C1 consisted of largely ABC-DLBCLs with genetic features of an extra-follicular, possibly marginal zone origin.
C2 included both ABC and GCB DLBCLs with biallelic inactivation of TP53, 9p21.3/CDKN2A, and associated genomic instability.
Most DLBCLs in C3 were of the GCB subtype and were characterized by BCL2 structural variants and alterations of PTEN and epigenetic enzymes.
C4 consisted largely of GCB DLBCLs with alterations in BCR/PI3K, JAK/STAT, and BRAF pathway components and multiple histones.
Most C5 DLBCLs were of the ABC subtype, and the researchers said the major components of the C5 signature—BCL2 gain, concordant MYD88L265P/CD79B mutations, and mutations of ETV6, PIM1, GRHPR, TBL1XR1, and BTG1—were similar to those observed in primary central nervous system and testicular lymphoma.
Dr Shipp and her colleagues also identified a sixth cluster of DLBCLs (dubbed C0) that “lacked defining genetic drivers.”
Finally, the team found that patients with C0, C1, and C4 DLBCLs had more favorable outcomes, while patients with C2, C3, and C5 DLBCLs had less favorable outcomes.
“We feel this research opens the door to a whole series of additional investigations to understand how the combinations of these genetic alterations work together, and then to use that information to benefit patients with targeted therapies,” Dr Shipp said.
She and her colleagues are now working on creating a clinical tool to identify these genetic signatures in patients. The team is also developing clinical trials that will match patients with given genetic signatures to targeted treatments.
Another group of researchers recently identified 4 genetic subtypes of DLBCL.
New research has revealed 5 genetic subtypes of diffuse large B-cell lymphoma (DLBCL).
Researchers identified a group of low-risk activated B-cell (ABC) DLBCLs, 2 subsets of germinal center B-cell (GCB) DLBCLs, a group of ABC/GCB-independent DLBCLs, and a group of ABC DLBCLs with genetic characteristics found in primary central nervous system lymphoma and testicular lymphoma.
The researchers believe these findings may have revealed new therapeutic targets for DLBCL, some of which could be inhibited by drugs that are already approved or under investigation in clinical trials.
Margaret Shipp, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and her colleagues conducted this research and reported the results in Nature Medicine.
The team performed genetic analyses on samples from 304 DLBCL patients and observed great genetic diversity. The median number of genetic driver alterations in individual tumors was 17.
The researchers integrated data on 3 types of genetic alterations—recurrent mutations, somatic copy number alterations, and structural variants—to define previously unappreciated DLBCL subtypes.
“Specific genes that were perturbed by mutations could also be altered by changes in gene copy numbers or by chromosomal rearrangements, underscoring the importance of evaluating all 3 types of genetic alterations,” Dr Shipp noted.
“Most importantly, we saw that there were 5 discrete types of DLBCL that were distinguished one from another on the basis of the specific types of genetic alterations that occurred in combination.”
The researchers classified these subtypes as clusters (C) 1 to 5.
C1 consisted of largely ABC-DLBCLs with genetic features of an extra-follicular, possibly marginal zone origin.
C2 included both ABC and GCB DLBCLs with biallelic inactivation of TP53, 9p21.3/CDKN2A, and associated genomic instability.
Most DLBCLs in C3 were of the GCB subtype and were characterized by BCL2 structural variants and alterations of PTEN and epigenetic enzymes.
C4 consisted largely of GCB DLBCLs with alterations in BCR/PI3K, JAK/STAT, and BRAF pathway components and multiple histones.
Most C5 DLBCLs were of the ABC subtype, and the researchers said the major components of the C5 signature—BCL2 gain, concordant MYD88L265P/CD79B mutations, and mutations of ETV6, PIM1, GRHPR, TBL1XR1, and BTG1—were similar to those observed in primary central nervous system and testicular lymphoma.
Dr Shipp and her colleagues also identified a sixth cluster of DLBCLs (dubbed C0) that “lacked defining genetic drivers.”
Finally, the team found that patients with C0, C1, and C4 DLBCLs had more favorable outcomes, while patients with C2, C3, and C5 DLBCLs had less favorable outcomes.
“We feel this research opens the door to a whole series of additional investigations to understand how the combinations of these genetic alterations work together, and then to use that information to benefit patients with targeted therapies,” Dr Shipp said.
She and her colleagues are now working on creating a clinical tool to identify these genetic signatures in patients. The team is also developing clinical trials that will match patients with given genetic signatures to targeted treatments.
Another group of researchers recently identified 4 genetic subtypes of DLBCL.
New research has revealed 5 genetic subtypes of diffuse large B-cell lymphoma (DLBCL).
Researchers identified a group of low-risk activated B-cell (ABC) DLBCLs, 2 subsets of germinal center B-cell (GCB) DLBCLs, a group of ABC/GCB-independent DLBCLs, and a group of ABC DLBCLs with genetic characteristics found in primary central nervous system lymphoma and testicular lymphoma.
The researchers believe these findings may have revealed new therapeutic targets for DLBCL, some of which could be inhibited by drugs that are already approved or under investigation in clinical trials.
Margaret Shipp, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and her colleagues conducted this research and reported the results in Nature Medicine.
The team performed genetic analyses on samples from 304 DLBCL patients and observed great genetic diversity. The median number of genetic driver alterations in individual tumors was 17.
The researchers integrated data on 3 types of genetic alterations—recurrent mutations, somatic copy number alterations, and structural variants—to define previously unappreciated DLBCL subtypes.
“Specific genes that were perturbed by mutations could also be altered by changes in gene copy numbers or by chromosomal rearrangements, underscoring the importance of evaluating all 3 types of genetic alterations,” Dr Shipp noted.
“Most importantly, we saw that there were 5 discrete types of DLBCL that were distinguished one from another on the basis of the specific types of genetic alterations that occurred in combination.”
The researchers classified these subtypes as clusters (C) 1 to 5.
C1 consisted of largely ABC-DLBCLs with genetic features of an extra-follicular, possibly marginal zone origin.
C2 included both ABC and GCB DLBCLs with biallelic inactivation of TP53, 9p21.3/CDKN2A, and associated genomic instability.
Most DLBCLs in C3 were of the GCB subtype and were characterized by BCL2 structural variants and alterations of PTEN and epigenetic enzymes.
C4 consisted largely of GCB DLBCLs with alterations in BCR/PI3K, JAK/STAT, and BRAF pathway components and multiple histones.
Most C5 DLBCLs were of the ABC subtype, and the researchers said the major components of the C5 signature—BCL2 gain, concordant MYD88L265P/CD79B mutations, and mutations of ETV6, PIM1, GRHPR, TBL1XR1, and BTG1—were similar to those observed in primary central nervous system and testicular lymphoma.
Dr Shipp and her colleagues also identified a sixth cluster of DLBCLs (dubbed C0) that “lacked defining genetic drivers.”
Finally, the team found that patients with C0, C1, and C4 DLBCLs had more favorable outcomes, while patients with C2, C3, and C5 DLBCLs had less favorable outcomes.
“We feel this research opens the door to a whole series of additional investigations to understand how the combinations of these genetic alterations work together, and then to use that information to benefit patients with targeted therapies,” Dr Shipp said.
She and her colleagues are now working on creating a clinical tool to identify these genetic signatures in patients. The team is also developing clinical trials that will match patients with given genetic signatures to targeted treatments.
Another group of researchers recently identified 4 genetic subtypes of DLBCL.