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Follicular Lymphoma Profiling Uncovers Recurrent Mutations, Patterns of Evolution

NEW YORK (GenomeWeb Daily News) – Follicular lymphomas exhibit certain recurrent mutations and hew to common patterns as they undergo transformation, according to a new study published in Nature Genetics yesterday.

Researchers led by Jude Fitzgibbon, a personalized cancer medicine professor at Queen Mary University of London, performed whole-genome or –exome sequencing on 10 follicular lymphoma–transformed follicular lymphoma pairs, and found that the tumors tended to follow one of two patterns of evolution, though both included the development of mutations in histone-modifying genes. Other recurrent mutations were found in linker histone, JAK-STAT, and B-cell development-related genes. By following lymphomas over time, the researchers also uncovered changes to chromatin regulatory genes that appeared to be early driver mutations as well as mutations in NF-κB signaling regulatory genes that seemed to arise at transformation.

"The mutational landscape of follicular lymphoma predominantly indicates epigenetic 'addiction,' but highlights co-occurring aberrations in genes involved in B-cell development as well as JAK-STAT and NF-κB signaling," Fitzgibbon and his colleagues wrote. "By longitudinal profiling, we provide unequivocal evidence for a reservoir ancestral population, enriched in early mutations in driver genes, that propagates successive disease events."

About one in five lymphomas in the US are follicular lymphomas, and, of those, about one in three develop into the more aggressive diffuse B-cell lymphoma, according to the American Cancer Society.

In this study, the researchers sought to uncover the genetic events that underlie that transition. For those 10 pairs of 10 follicular lymphoma–transformed follicular lymphoma cases, the researchers sequenced either the whole genome or whole exome using the Illumina HiSeq 2000 platform or HiSeq2500, respectively, to yield a mean 37x genomic and 110x exonic coverage, and 96 percent of the targeted bases had more than 10-fold coverage.

For the six cases that underwent whole-genome sequencing, the researchers noted some 10,000 somatic variants per tumor, and between 21 and 143 nonsynonymous somatic variants per sample that appear to be protein-changing variants.

To trace how these variants arose in the various samples, Fitzgibbon and his colleagues drew up phylogenetic trees for each case using a neighbor-joining algorithm. By examining the trees, they saw two distinct patterns of evolution.

In one, the researchers noted that there was high clonal similarity between the follicular lymphoma–transformed follicular lymphoma pairs and that certain recurrent mutations were shared among the common progenitor clones. Those mutations, which were enriched for genes involved in chromatin regulations, included KMT2D, CREBBP, EP300, and MEF2B. Other common mutations affected the immune genes B2MCD58 and TNFRSF14; the JAK-STAT signaling genes OCS1 and STAT6; and the B-cell receptor-NF-κB signaling genes BCL10, CARD11, and CD79B.

The other pattern contained comparably fewer mutations, with the pairs exhibiting four nonsynonymous mutations. Additionally, three of those genes — CREBBP, KMT2D, and TNFRSF14 — had different mutations before and after transformation.

"These observations strongly support tumoral dependency on CREBBP, KMT2D, and TNFRSF14 alterations during lymphomagenesis and progression," the researchers noted.

They explored the prevalence of the mutations they had identified by drawing on a further 100 follicular lymphoma biopsies and 32 paired follicular lymphoma–transformed follicular lymphoma cases for targeted re-sequencing of 28 genes, again finding a number of mutations affecting chromatin regulation.

More than 70 percent of the cases had mutations in at least two of the histone-modifying enzymes — CREBBP, EZH2, MEF2B, and KMT2D — examined. In addition, they noted that linker histone genes were recurrently mutated in the disease. Nearly a third of the samples had mutations affecting at least one histone H1 gene, the researchers reported. Using H1 triple knockout mice, they found that the p.Ser102Phe mutation leads to impaired association with chromatin, which the researchers said likely also leads to a loss-of-function phenotype by affecting binding affinity.

Additionally, they noted a number of mutations in the JAK-STAT pathway as well as mutations leading to the constitutive activation of the antipoptotic NF-κB signaling pathway and mutations affecting B-cell development, especially EBF1.

Mutations in histone-modifying genes as well as in STAT6 and TNFRSF14 appeared to be driver mutations, Fitzgibbon and his colleagues said. Additionally, by looking at the samples over time, they noted that those mutations remained constant, even during therapeutic interventions, and added that this underscored that these mutations were key events in the common progenitor clone.

A number of mutations also appeared to be acquired during the transformation process, including ones in EB1 and MYD88.

"The acquisition of these late genetic events underscores the need for temporal mutational profiling as we move toward an era of precision medicine," Fitzgibbon and his colleagues said.

There doesn't appear to be a single event that leads to transformation, though the researchers noted that certain genetic changes seem to precede the onset of aggressive disease.

"The high frequency of relapse suggests that [common progenitor clones] are resistant to standard therapies and that adopt¬ing a stratified treatment approach targeting the specific early genetic lesions identified in the putative CPC may ultimately offer the best chance of eradicating these cells and curing follicular lymphoma," they added.