Histones Unexpectedly Identified as Playing a Role in Non- Hodgkin’s Lymphoma

Scientists at the University of British Columbia have found that histone-modifying genes are often mutated in non-Hodgkin’s lymphoma (NHL). The results of the study were published on July 27, 2011 on the journal Nature’s website ahead of print (DOI: 10.1038/nature10351).

Marco A. Marra at Canada’s Michael Smith Genome Sciences Centre in British Columbia and the University of British Columbia and his colleagues sequenced both follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), the two most common types of NHL, and matched normal DNA from 14 cases of FL and DLBCL cases. The comparison identified genes that are mutated in B-cell NHL. The team analyzed RNA sequencing data from these samples as well as 113 others to identify other candidate mutated genes, confirming 109 genes with multiple somatic mutations.

Image of a nucleosome. Molecular surface of histones is shown in white and the two strands of DNA in red and blue.

Most of these genes have not been previously implicated in cancer pathways. According to the authors, “mutation hot spots can result from mutations at sites under strong selective pressure” and the RNA sequencing method used in this research was previously used to identify these hot spots in NHL. The found mutations were validated by sequencing each analyzed gene from tumor samples. 

Interestingly, genes with roles in histone modification were frequently found to have multiple somatic mutations in tumors. 32% of DLBCL and 89% of FL cases had mutations in a methyltransferase, MLL2. MLL2 also had the most significant evidence for selection as well as the largest number of nonsense single nucleotide variant mutations. In total, about half of the tumors sequenced had at least two mutations in this gene. Subsequent analysis by Marra predicted that the majority of somatic mutaitons in MLL2 were inactivating (either disrupted reading frame or truncating point mutations), signifying that the gene is a tumor suppressor that is significant for NHL development. 

Providing further evidence that MLL2 is a cancer gene, MLL2 mutations have recently been reported in a small-cell lung cancer cell line as well as in renal, and inactivating mutations have also been seen in medulloblastoma patients. 

The analysis also found that 11.4% and 13.4% of DLBCL and FL cases, respectively, had mutations in a calcium-regulated gene, MEF2B, that functions along with CREBBP and EP300 in acetylating histones. In contrast to nonsense mutations in MLL2, the mutations seen in MEF2B were amino acid substitutions.

The group was able to distinguish cancer-related genes or candidate cancer driver genes from mutations that are merely “passengers” and do not facilitate tumor development and evolution. Twenty-six such genes were identified and included known lymphoma driver mutations such as BCL2 and EZH2, validating the approach.

The study results suggest a “previously unappreciated disruption of chromatin biology in lymphomagenesis” according to the authors.