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Photo courtesy of Dana-
Farber Cancer Institute
Researchers say they have identified dozens of genetic abnormalities that may drive chronic lymphocytic leukemia (CLL), including some that were never before linked to human cancer.
The team began to trace how some of these abnormalities affect the course of the disease and its susceptibility to treatment.
And they started tracking the evolutionary path of CLL as its genome spawns new groups and subgroups of tumor cells in a single patient.
“Sequencing the DNA of CLL has taught us a great deal about the genetic basis of the disease,” said Catherine Wu, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.
“Previous studies, however, were limited by the relatively small number of tumor tissue samples analyzed and by the fact that those samples were taken at different stages of the treatment process from patients treated with different drug agents.”
“In our new study, we wanted to determine if analyzing tissue samples from a large, similarly treated group of patients provides the statistical power necessary to study the disease in all its genetic diversity, to draw connections between certain mutations and the aggressiveness of the disease, and to chart the emergence of new mutations and their role in helping the disease advance. Our results demonstrate the range of insights to be gained by this approach.”
Dr Wu and her colleagues reported these results in Nature.
The researchers collected tumor and normal tissue samples from 538 patients with CLL and performed whole-exome sequencing on each sample.
In this way, the team identified 44 putative CLL driver genes, including 18 CLL mutated drivers that were previously identified and 26 additional putative CLL genes. About 34% of the CLL samples harbored a mutation in at least 1 of these 26 genes.
Nearly 9% of the patients had mutations in CLL genes in the MAPK-ERK pathway. The researchers therefore believe that further exploration of MAPK-ERK pathway inhibitors may be warranted.
The team found that mutations differed between IGHV-mutated and unmutated CLL. IGHV-unmutated CLL tended to have a higher proportion of most driving mutations, while only 3 driver genes were enriched in IGHV-mutated CLL—del(13q), MYD88, and CHD2.
The researchers also discovered that certain mutations were common in patients who had already undergone treatment.
Previous treatment was associated with enrichment in TP53 and BIRC3 mutations del(17p) and del(11q), as well as in mutated DDX3X and MAP2K1. The team therefore believes these mutations may help CLL rebound after initial therapy.
Another key finding was that therapy tended to produce shorter remissions in patients with mutations in TP53 or SF3B1.
“We found that genomic evolution after therapy is the rule rather than the exception,” Dr Wu noted. “Certain mutations were present in a greater number of leukemia cells within a sample after relapse, showing that these mutations, presumably, allow the tumor to persevere.” 
Photo courtesy of Dana-
Farber Cancer Institute
Researchers say they have identified dozens of genetic abnormalities that may drive chronic lymphocytic leukemia (CLL), including some that were never before linked to human cancer.
The team began to trace how some of these abnormalities affect the course of the disease and its susceptibility to treatment.
And they started tracking the evolutionary path of CLL as its genome spawns new groups and subgroups of tumor cells in a single patient.
“Sequencing the DNA of CLL has taught us a great deal about the genetic basis of the disease,” said Catherine Wu, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.
“Previous studies, however, were limited by the relatively small number of tumor tissue samples analyzed and by the fact that those samples were taken at different stages of the treatment process from patients treated with different drug agents.”
“In our new study, we wanted to determine if analyzing tissue samples from a large, similarly treated group of patients provides the statistical power necessary to study the disease in all its genetic diversity, to draw connections between certain mutations and the aggressiveness of the disease, and to chart the emergence of new mutations and their role in helping the disease advance. Our results demonstrate the range of insights to be gained by this approach.”
Dr Wu and her colleagues reported these results in Nature.
The researchers collected tumor and normal tissue samples from 538 patients with CLL and performed whole-exome sequencing on each sample.
In this way, the team identified 44 putative CLL driver genes, including 18 CLL mutated drivers that were previously identified and 26 additional putative CLL genes. About 34% of the CLL samples harbored a mutation in at least 1 of these 26 genes.
Nearly 9% of the patients had mutations in CLL genes in the MAPK-ERK pathway. The researchers therefore believe that further exploration of MAPK-ERK pathway inhibitors may be warranted.
The team found that mutations differed between IGHV-mutated and unmutated CLL. IGHV-unmutated CLL tended to have a higher proportion of most driving mutations, while only 3 driver genes were enriched in IGHV-mutated CLL—del(13q), MYD88, and CHD2.
The researchers also discovered that certain mutations were common in patients who had already undergone treatment.
Previous treatment was associated with enrichment in TP53 and BIRC3 mutations del(17p) and del(11q), as well as in mutated DDX3X and MAP2K1. The team therefore believes these mutations may help CLL rebound after initial therapy.
Another key finding was that therapy tended to produce shorter remissions in patients with mutations in TP53 or SF3B1.
“We found that genomic evolution after therapy is the rule rather than the exception,” Dr Wu noted. “Certain mutations were present in a greater number of leukemia cells within a sample after relapse, showing that these mutations, presumably, allow the tumor to persevere.”
Photo courtesy of Dana-
Farber Cancer Institute
Researchers say they have identified dozens of genetic abnormalities that may drive chronic lymphocytic leukemia (CLL), including some that were never before linked to human cancer.
The team began to trace how some of these abnormalities affect the course of the disease and its susceptibility to treatment.
And they started tracking the evolutionary path of CLL as its genome spawns new groups and subgroups of tumor cells in a single patient.
“Sequencing the DNA of CLL has taught us a great deal about the genetic basis of the disease,” said Catherine Wu, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.
“Previous studies, however, were limited by the relatively small number of tumor tissue samples analyzed and by the fact that those samples were taken at different stages of the treatment process from patients treated with different drug agents.”
“In our new study, we wanted to determine if analyzing tissue samples from a large, similarly treated group of patients provides the statistical power necessary to study the disease in all its genetic diversity, to draw connections between certain mutations and the aggressiveness of the disease, and to chart the emergence of new mutations and their role in helping the disease advance. Our results demonstrate the range of insights to be gained by this approach.”
Dr Wu and her colleagues reported these results in Nature.
The researchers collected tumor and normal tissue samples from 538 patients with CLL and performed whole-exome sequencing on each sample.
In this way, the team identified 44 putative CLL driver genes, including 18 CLL mutated drivers that were previously identified and 26 additional putative CLL genes. About 34% of the CLL samples harbored a mutation in at least 1 of these 26 genes.
Nearly 9% of the patients had mutations in CLL genes in the MAPK-ERK pathway. The researchers therefore believe that further exploration of MAPK-ERK pathway inhibitors may be warranted.
The team found that mutations differed between IGHV-mutated and unmutated CLL. IGHV-unmutated CLL tended to have a higher proportion of most driving mutations, while only 3 driver genes were enriched in IGHV-mutated CLL—del(13q), MYD88, and CHD2.
The researchers also discovered that certain mutations were common in patients who had already undergone treatment.
Previous treatment was associated with enrichment in TP53 and BIRC3 mutations del(17p) and del(11q), as well as in mutated DDX3X and MAP2K1. The team therefore believes these mutations may help CLL rebound after initial therapy.
Another key finding was that therapy tended to produce shorter remissions in patients with mutations in TP53 or SF3B1.
“We found that genomic evolution after therapy is the rule rather than the exception,” Dr Wu noted. “Certain mutations were present in a greater number of leukemia cells within a sample after relapse, showing that these mutations, presumably, allow the tumor to persevere.”