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Researchers Pinpoint Mutations, Copy Number Changes in Lymphoma Subtypes

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Diffuse large B-cell lymphoma is characterized by sub-type specific mutations and copy number changes as well as genetic lesions that show across DLCBL sub-types, according to a study appearing online this past weekend in Nature Genetics.

American and Italian researchers did exome sequencing and microarray analyses on matched tumor-normal samples from six individuals to identify somatic mutations and copy number changes involved in samples from several sub-types of the disease. The search unearthed mutations in several genes not previously implicated in the disease, including some from chromatin methylation and immune related pathways.

"The present study was aimed at expanding our current knowledge of the number and type of genetic alterations that are present in the DLBCL coding genome by integrating massively parallel whole-exome sequencing and genome-wide high-density SNP array analysis," co-corresponding author Riccardo Dalla-Favera, a cancer genetics researcher at Columbia University, and his co-authors wrote.

"This combined approach allowed the definition of the degree of complexity characterizing the DLBCL coding genome," they added, "and revealed the involvement of several previously unrecognized dysregulated genes and pathways."

Together, their results suggest that DLBCL tumors contain some genetic alterations that are common to all sub-sets of the disease, such as mutations affecting chromatin modification genes, as well as others that are specific to certain sub-types.

"The observed distribution [of recurrent genetic lesions] has immediate clinical implications," Dalla-Favera and colleagues noted, "as it suggests the development of therapies that combine drugs targeting commonly altered pathways with those targeting pathways selectively disrupted in DLBCL sub-types."

DLBCL cases can be subdivided into sub-groups depending on the stage of differentiation at which B cells are affected, the study authors explained. Past studies suggest that these various subsets of DLBCL may harbor different mutation profiles ranging from NF-kappa B transcription complex activation or acetyltransferase gene inactivation to CD273 and CD274 rearrangements and amplification, they noted, though many genetic changes remain to be found.

"Major improvements in sequencing technologies have now provided an unprecedented opportunity to examine the cancer genome for large-scale identification of genomic alterations in a comprehensive and unbiased manner," the researchers wrote.

For the current study, researchers examined several DLBCL sub-types, using samples from three individuals with a DLBCL sub-type known as activated B-cell-like (ABC) DLBCL, one individual with so-called germinal-center B-cell-like (GCB) DLBCL, one with non-GCB DLBCL, and another with an unclassified form of the disease.

After capturing non-repetitive protein-coding sequencing with the NimbleGen Sequence Capture Human Exome 2.1M array, the team sequenced the exomes with the Roche 454 GS FLX. They also did targeted exon sequencing for a handful of suspicious genes not captured by the array.

The researchers also used Affymetrix SNP 6.0 arrays to profile copy number patterns in the matched tumor-normal samples before screening 73 more DLBCL tumor samples obtained from biopsies.

Overall, the researchers detected dozens of genetic glitches per case, affecting many of the genes previously been linked to DLBCL as well as a slew of new genes and pathways.

And although the mutation and copy number patterns varied with DLBCL sub-type and from one individual to the next, the team did see some recurrent mutations. For instance, nearly a quarter of the samples tested (24 percent) harbored mutations in the histone methylation gene MLL2. Researchers also saw recurrent changes to genes contributing immune system function, particularly T cell-based immune recognition.

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