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Mutations Affecting Histones Could Contribute to Tumorigenesis, New Study Finds

NEW YORK (GenomeWeb) – Mutations affecting histones occur in about 4 percent of tumors, according to a new analysis appearing in Nature today.

Mutations affecting epigenetic pathways are common drivers of cancer, and some of these, researchers from Memorial Sloan Kettering Cancer Center noted, affect histones themselves.

They relied on publicly available tumor sequencing databases and data from the MSK-IMPACT sequencing effort to survey what histone mutations are present in a range of human cancers. As they reported in their new paper, Sloan Kettering's David Allis and his colleagues uncovered more than 4,200 histone missense mutations, many of which might affect chromatin or epigenetic functions.

"Given the key role that histones have in cell fate and differentiation as the substrates for epigenetic machinery, histone mutations may cause the dysregulation of these processes, a step central to oncogenesis," they wrote in their paper.

In particular, the researchers identified 4,205 histone mutations within 3,143 samples, and these mutations affect all the core histone families. Within the MSK-IMPACT dataset alone, 3.8 percent of tumor samples harbored histone missense mutations. That percentage, they noted, is about the same as the prevalence of BRCA2, TET2, SMAD4, and NOTCH1 somatic mutations in the cohort.

These oncohistone mutations included known ones like H3(K27M) and H3(G34R/V) in gliomas, H3(G34W) in osteosarcomas, and H3(K36M) in head and neck cancers. They also noted, though, that some of these oncohistone mutations cropped up in other cancer types, such as H3(K36M) in melanoma, bladder cancer, and colorectal cancer.

Through unsupervised hierarchal clustering, the researchers found that mutations can crop up at residues independently of tumor type, though they noted that some patterns do appear to be tumor-type specific. For instance, they found that the H3 mutational patterns observed in pancreatic cancer different from those seen in cervical cancer.

The researchers also traced many of these oncohistone mutations to N-terminal tail domains and globular domains of histones, and suggested that N-terminal tail mutations could affect the chromatin machinery that operates there.

Previous yeast studies had uncovered mutations within H3 and H4 that eliminate the need for the SWI/SNF remodeling complex to regulate gene expression, the researchers noted. They added that these Sin- mutations tend to occur in the globular domains of H3 and H4 — including at one of the most commonly altered residues altered in cancer dataset. As the SWI/SNF complex is involved in the regulation of gene expression, this suggested to the researchers that, in tumors, these mutations could lead to the aberrant expression of oncogenes or developmental genes.

The researchers additionally reported on a number of mutations affecting the so-called acidic patch formed by six H2A and two H2B residues within the nucleosome anchoring point. They predicted that mutations affecting this region could influence chromatin condensation and folding, nucleosome remodeling, DNA damage repair, and other functions.

They likewise noted a number of mutations within the globular core domain that could affect the 3D structure of the histone, including at H2A and H2B.

Based on their findings, Allis and his colleagues proposed a model in which an oncohistone mutation can lead to tumorigenesis by altering the biophysical conformation or functional properties of chromatin. They further suggested that these oncohistone mutations could have dominant effects.

"Although many of the mutations in the dataset may ultimately be passengers, the nature of a subset of the mutations that we analyzed has enabled us to generate testable hypotheses about possible functional roles of these oncohistones in tumorigenesis," the researchers wrote. "Understanding mechanisms that underlie a subset of these mutations may reveal how disrupting histone or nucleosomal function may contribute to oncogenic transformation."