Understanding these changes could lead to strategies for treating the disease, Dr. Marco Marra of the BC Cancer Agency in Vancouver and his colleagues reported online in Nature on July 27.
To learn more about the biology of NHL, the researchers sequenced the genomes of 13 patients with diffuse large B-cell lymphoma and one with follicular lymphoma—the two most common forms of NHL. After surveying the genetic changes in another 113 NHL cases, the researchers identified 26 genes with recurrent mutations that could be involved in cancer.
Five of the most commonly mutated genes encode proteins that are involved in the chemical modification of histones, which are chromatin proteins responsible for packaging DNA. When histones are modified, the DNA in chromatin is packaged less tightly and gene expression is facilitated; when histone modifications are removed, the DNA becomes more tightly packaged and gene expression is suppressed. Thus, proteins involved in histone modification can alter the activity of genes across the genome.
Mutations in one of the five genes, MLL2, were identified in 89 percent of the patients with follicular lymphoma, which would make it one of the most commonly mutated genes in NHL. Noting that the gene is mutated in other cancers as well, the study’s authors suggested that the MLL2 protein may normally help suppress tumor formation.
The second mutated gene the authors highlighted, MEF2B, had not previously been linked to cancer, but the pattern of mutations in this gene resembled patterns found in other known cancer-related genes. Based on their findings, the researchers concluded that the mutation of genes involved in histone modification is likely to be a central event in the development of some forms of NHL.
These findings confirm and extend recent reports of mutations in histone-related genes in NHL (here and here). Similar genetic alterations have also been found in a form of kidney cancer and the childhood cancer medulloblastoma. Drugs with the potential to reverse epigenetic changes in cells, such as histone modifications, are available, but some researchers caution that the relationship between the recently identified mutations and cancer is unclear.
“This study opens quite a few new avenues for researchers by introducing a list of genes that no one had thought would be involved in these diseases,” said the first author, Ryan Morin of the BC Cancer Agency. And because certain mutations were found in only some subtypes of NHL, the alterations, if confirmed, could help doctors diagnose the disease and select the most appropriate therapies, he added.
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