Histone Mutation Associated with Pediatric Cancer Development

Study finds PRC2 inhibitor may treat wide range of cancer types.

A link was found between pediatric cancers and a single defect in a gene that codes for a histone, a study published in Science found.

“Unlike most cancers that require multiple hits, we found that this particular mutation can form a tumor all by itself,” said researcher Peter W. Lewis.

In 2013, Lewis and his colleagues discovered that the mechanism for a histone mutation was linked to DIPG, a fatal brain tumor. These mutations can cause a histone to inhibit PRC2, which inactivates genes by compacting them.

During the current study, researchers were able to show just how powerful the histone mutation is.

“No one had ever thought that a single histone mutation would be found to cause cancer, because you get 15 copies of the histone gene from each parent,” Lewis said.

Although in prior work, the mutations caused the histone to inhibit PRC2, this action doesn’t occur if the PRC2 itself is not inhibited by a histone mutation, which leads to aberrant gene expression. This act of gene silencing is necessary, and although nearly all human cell types contain every one of the 20,000-odd genes, most are shut off in any given cell type because they are packed up and aren’t able to act as a template for proteins, Lewis stated.

Research conducted in 2014 revealed that a K27 mutation could block differentiation of a neural stem cell, causing it to remain in a primitive state prone to uncontrolled growth. A research group in the United Kingdom found that 95% of chondroblastomas contained a similar mutation at K36 on the histone gene.

The primary focus of the current study was on the K36 mutation, which blocks the specialization of the type of stem cell that is able to form bone, cartilage, and fat. The mutation was inserted into mice resulting in an undifferentiated pediatric sarcoma.

While screening human tissues from undifferentiated sarcomas, researchers found the same K36 mutations in 20% of the samples they tested.

“What we were learning in mice was reflected in human disease, it was not just some weird mouse artifact,” Lewis said.

There are few gene mutations that have the ability to cause cancer on their own, but for the first time the histone gene mutation showed it had the ability to cause cancer by itself.

“(The results were even more interesting) because there are 29 intact histone genes, and other mutations that are normally present in adult tumors were absent,” Lewis said. “This is what we call a dominant negative; it's the rotten apple that spoils the barrel. These are very potent mutations.”

According to researchers, the enzymes that were affected by the histone mutations have been implicated in many common forms of cancer. In fact, a drug that inhibits PRC2 could have the ability to treat breast cancer.