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Sequencing of CLL Patients Enables Stratification and IDs Potential Drug Targets

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By Monica Heger

Sequencing chronic lymphocytic leukemia patients from two clinical subtypes could enable molecular stratification of those patients, and may eventually lead to personalized treatment based on the tumor subtype, according to new research from the University of Barcelona.

The researchers sequenced four CLL patients, identifying recurrent mutations in four different genes, including a potential target for drugs currently in development for other cancers. The patients also had two distinct mutational profiles, corresponding with clinical outcomes.

The study, which was done as part of the International Cancer Genome Consortium and published in Nature this week, highlights the clinical importance of cancer genome sequencing.

The team, which used whole-genome sequencing, whole-exome sequencing, and long-insert paired-end libraries to detect structural variations on the Illumina Genome Analyzer, was able to stratify the patients based on their specific clinical subtype of CLL — one associated with a better prognosis that typically involves mutations to immunoglobulin genes, and one associated with a poor prognosis that does not contain mutations to those genes.

Elias Campo, chief of the hematopathology unit at the University of Barcelona and senior author of the study, said they specifically chose two patients from each subtype to see if sequencing would illuminate the molecular changes that characterize their differences.

The study suggests that "the clinical heterogeneity might be related to different somatic mutations in different genes," he said.

CLL can currently be subtyped according to clinical outcome and markers such as mutations in the immunoglobulin genes. However, these mutations are not thought to be "fundamental agents in the leukemic process," the authors wrote, and do not help in understanding the etiology of cancer, improving diagnostics, or in designing better therapies.

Being able to genomically characterize the subtypes, on the other hand, could lead to better diagnostics and patient stratification, and could also suggest new drug targets, Campo said.

Campo and his team sequenced the whole genomes of four patients, and identified 46 somatic mutations that potentially affected gene function. They screened for those mutations in an additional 363 patients using a pooled sequencing approach, and identified four genes that are recurrently mutated: NOTCH1, XPO1, MYD88, and KLHL6.

Mutations in the NOTCH1 and XPO1 genes were associated with poor prognosis and patients without mutations to the immunoglobulin genes, while mutations to the MYD88 and KLHL6 genes were associated with the other subtype.

Additionally, said Campo, there are currently drugs under development for other cancers that target the NOTCH1 gene. Mutations to that gene were found in 20.4 percent of patients with the unmutated immunoglobulin genes.

While some of these drugs have been studied in clinical trials, they are not approved for treatment. However, he said his team has started doing "in vitro testing and clinical assays to test the potential use of the drugs in CLL."

While the results need to be confirmed, Campo said they could lead to a better understanding of the different subtypes, better patient stratification, and eventually new therapeutics.

Currently, most CLL patients receive the same treatment regimen, he said. But if the function of the mutations can be determined, and targeted therapies can be developed for specific molecular alterations, the results could help move toward personalized treatment, he said.

In order to further characterize the mutations, the team performed a functional analysis of the NOTCH1 and the MYD88 mutations in the primary cells. The team focused on these mutations first, said Campo, because the other two "are new genes mutated in cancer, and not much information about the functional effects is available." However, he said they plan to follow up on those mutations.

Mutations in the NOTCH1 gene generate a premature stop codon, resulting in a more stable and active isoform of the protein, leading the researchers to suspect that the mutated NOTCH1 acts as an oncogene. A gene expression analysis of both mutated and unmutated NOTCH1 cases found 23 of the 46 genes in the pathway were differentially expressed. Additionally, NOTCH1 mutated patients had a poorer prognosis, with a 10 year survival rate of just 21 percent, compared to 56 percent in the non-NOTCH1 mutated patients. The NOTCH1 mutated patients were also more likely to have a more advanced stage of the disease at diagnosis and showed more adverse clinical features. They were also most likely to go on to develop B-cell lymphoma.

The team also concluded that mutations to MYD88 were oncogenic. The same mutation has been identified in other lymphomas, and the protein is involved in signaling pathways during immune response. Patients with MYD88 were from the subtype with a better prognosis, yet patients with the MYD88 mutation tended to develop cancer earlier.

"The disease usually occurs in the elderly, but patients with this mutation are younger than 50," Campo said. "So this may be associated with a younger onset of the disease."

Campo said that the team is now en route toward sequencing 500 whole genomes of CLL patients as their contribution to the ICGC and this study represents the beginning of that work. "It confirms that this approach might pay off," he added.


Have topics you'd like to see covered by Clinical Sequencing News? Contact the editor at mheger [at] genomeweb [.] com.

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