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Spanish-led Team Profiles Mantle Cell Lymphoma Mutations

NEW YORK (GenomeWeb News) – A team from Spain, Germany, and the US has used genome, exome, and targeted sequencing to take a look at mutational patterns in mantle cell lymphoma.

As they reported online in the Proceedings of the National Academy of Sciences last night, the researchers did exome sequencing on tumor and normal samples from 29 individuals with MCL and whole-genome sequencing on four tumor-normal pairs. Together with exome sequencing on six cell lines and targeted sequencing on MCL samples from 172 more individuals, that search led to more than two-dozen significantly mutated genes, including some that appear to provide prognostic information on a subset of MCL cases.

By sequencing multiple samples from the same individuals at one or more time points, meanwhile, the team began defining subclonal populations within MCL tumors and following the accumulation of new mutations in progressive disease over time.

In a statement the study's first author, Silvia Beà of the University of Barcelona, said the work "provides insights into causes and evolution of this complex neoplasm." She noted that the MCL study is also expected to serve as a resource for those seeking new therapeutic targets for the aggressive and tricky to treat blood and lymph node cancer.

The cancer, which affects mature B-cells, is often marked by a translocation that bumps up the expression of cyclin D1-coding gene CCND1, Beà and her co-authors explained. But while CCND1 contributes to MCL development, more research is needed to untangle the network of other alterations involved in that process and in the cancer's progression.

For their analysis, the researchers started by doing whole-exome sequencing on matched tumor-normal samples from 29 individuals with MCL as well as six cell lines.

Another four tumor-normal pairs were subjected to whole-genome sequencing, they explained, while array-based approaches were used to garner copy number profiles from exome-sequenced samples.

The team then sifted through this data — and targeted sequence information on another 172 MCL cases — to look for genes with recurrent alterations.

Along with known MCL contributors such as CCND1, TP53, and ATM, the significantly mutated gene set included genes not previously linked to the disease. In particular, the team's results suggested that the chromatin modifier genes WHSC1, MLL2, and MEF2B are altered in at least a small subset of MCL cases.

While NOTCH2 mutations were found in just one of the tumors sequenced initially, the researchers decided to broaden their search for alterations in that gene and in NOTCH1 using 172 MCL tumors from their validation set.

NOTCH1 and NOTCH2 mutations have been implicated in especially aggressive cases from other cancer types, they noted. And as such, they have become a focus for targeted treatment development in other areas of cancer research.

Indeed, NOTCH2 mutations turned up in more than 5 percent of MCL tumors tested for the study, while almost 5 percent of the MCL cases involved mutations to NOTCH1, study authors reported, noting that "[a]ll these [NOTCH1/2] mutations generated truncating and likely more active proteins and occurred in a subset of tumors with very aggressive clinical behavior."

The presence of mutations in the NOTCH1/2 and other genes described in chronic lymphocytic leukemia, splenic marginal zone lymphoma, diffuse large B-cell lymphoma, and the like points to the presence of some genetic overlap that exists across lymphoma, they noted.

The work also highlighted MCL subtypes containing mutations in characteristic genes and gene combinations. In tumors with enhanced expression of the SOX1 gene, for example, they often saw concurrent alterations affecting the CCND1 gene and/or chromatin modifier genes, while mutations in a handful of other genes tended to coincide with copy number changes involving portions of chromosomes 11 or 17.

But genetic diversity present in the MCL tumors, too, reflecting features related to subclonal heterogeneity and tumor evolution events.

By comparing two tumor samples collected from six individuals at the one time point and two tumor samples collected at the time of diagnosis and after disease progression in two more patients, the researchers were able to begin picking apart the order with which mutations appear in MCL and the events contributing to the cancer's progression.

"The sequence of two simultaneous or longitudinal samples in different topographic sites in our study has revealed that some tumors may have at least two major subclones already at diagnosis with different representation in two topographic sites, lymph nodes, and peripheral blood," the researchers reported.

"In addition, the evolution of the tumors is also heterogeneous," they noted, "with the eradication of some clones by the chemotherapy treatment and the [emergence] of other new clones at the progression of the disease or at relapse after chemotherapy."