Chromatin and cancer
A flurry of studies suggests mutations in chromatin remodeling proteins are a common cancer pathway
The evidence is growing: an increasing number of studies are implicating proteins involved in chromatin modification -- changes in the structure of chromosomes -- in numerous types of cancer.
"Suddenly, in the last six months, all this new data from cancers show the involvement of [mutated] chromatin enzymes," said linkurl:Bin Teh,;http://www.vai.org/research/labs/cancergenetics.aspx director of the laboratory of cancer genetics at the Van Andel Research Institute in Michigan. "I think a lot of people did not suspect chromatin enzymes were involved."
In early cancer genomics research in the 1980s and 1990s, scientists used family studies and linkage analyses to identify numerous tumor suppressor genes, such as p53, RB1, ATM, BRCA-1
that were often mutated in cancerous cells. Now, thanks to next generation technology enabling the rapid sequencing of an exome -- all the protein-coding regions in a genome -- scientists have expanded their search for cancer-causing genes, systematically exploring tumor tissue for somatic mutations. And time again and again, the data point to a new class of mutations -- those in chromatin remodeling genes.
"These mutations were all just sitting there, but we didn't have the means to see them," said linkurl:Steven Jones,;http://www.bcgsc.ca/faculty/sjones head of bioinformatics at Canada's Michael Smith Genome Sciences Centre in Vancouver. "It's amazing now how quickly we can now find some of these recurrent genes."
Many genes identified through exome sequencing of tumor tissue include histone modifiers, enzymes that change the conformation of histones, leading to misregulated gene expression. Other studies implicate histone proteins themselves. "In some sense, it's the same as a mutation in a signaling pathway -- a protein becomes dysfunctional in some way, shape or form," said linkurl:Emily Bernstein,;http://www.mountsinai.org/profiles/emily-bernstein who studies epigenetic regulation of gene expression in melanoma at the Mount Sinai School of Medicine in New York. "The difference is that these chromatin related proteins are directly regulating the genome."
In February 2010, Jones, along with linkurl:Marco Marra;http://www.bcgsc.ca/faculty/mmarra/ at the BC Cancer Agency in Canada, identified a specific and recurrent mutation -- the replacement of a single tyrosine -- in linkurl:EZH2, a gene encoding a histone methyltransferase.;http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2850970/?tool=pubmed The mutation, which results in reduced activity of EZH2 protein in vitro, occurs in 22 percent of diffuse large cell B-cell lymphomas and 7 percent of follicular lymphomas. "Most of these cancers still represent a black box in terms of the recurrent somatic mutations that they contain," said Jones. "It was surprising and exciting to find there seems to be a very specific change required in a subset of these tumors for oncogenesis."
Childhood brain tumors:
|Brain scan of six-year-old girl with a medulloblastoma |
linkurl:Wikimedia Commons, Reytan;http://commons.wikimedia.org/wiki/File:CompT1.jpg
In a linkurl:December Science paper;http://www.the-scientist.com/news/display/57866/, Victor Velculescu and colleagues at the Johns Hopkins Kimmel Cancer Center in Baltimore were surprised to find that the two most commonly mutated genes in medulloblastoma, the most common type of brain tumor in children, are histone methyltransferase genes linkurl:MLL2
;http://www.ncbi.nlm.nih.gov/pubmed/21163964 responsible for chromatin remodeling and transcriptional regulation. "These are master epigenetic controllers that regulate the activity of other genes," he told The Scientist
in December, "so it will be interesting going forward to figure out what are the genes that are normally regulated by MLL2 and MLL3. That may give us answers as to what additional mechanisms are important in these tumors."
Also in December, Bernstein and colleagues at Mount Sinai linkurl:reported that a histone protein;http://www.ncbi.nlm.nih.gov/pubmed/21179167 itself suppresses tumor progression of malignant melanoma, and the loss of the protein, called macroH2A, promotes tumor growth and metastasis by upregulating CDK8, a known oncogene.
In 2009, Teh and colleagues Michael Stratton and Andrew Futreal at the Wellcome Trust Sanger Institute in the UK got a tantalizing glimpse of linkurl:multiple histone modifiers;http://www.ncbi.nlm.nih.gov/pubmed/20054297 that appeared to be involved in clear cell renal cell carcinoma (ccRCC), the most common form of adult kidney cancer. "At the time, we found that they had a rather low frequency individually, but as a group, they contribute to about 15 percent" of ccRCC cases, said Teh. Last year, using more advanced sequencing methods, the team "found the big one," said Teh. Published linkurl:this January in Nature,
;http://www.ncbi.nlm.nih.gov/pubmed/21248752 the researchers identified mutations in PBRM1, a gene that encodes a subunit of a major chromatin remodeling complex, present in 41 percent of cases of ccRCC.
Most recently, in March, researchers at the Johns Hopkins Kimmel Cancer Center screened for commonly mutated genes in pancreatic neuroendocrine tumors, the second-most common form of pancreatic cancer. They found 44 percent of tumors had linkurl:inactivating mutations in MEN1,;http://www.ncbi.nlm.nih.gov/pubmed/21252315 which encodes a component of a histone methyltransferase complex, and 43 percent of tumors had mutations in one of two genes, DAXX or ATRX, that encode subunits for a chromatin remodeling complex. The results compliment linkurl:another recent study;http://www.ncbi.nlm.nih.gov/pubmed/20871795 that found that 98 percent of pancreatic neuroendocrine tumors show substantial chromosomal alternations.
Researchers predict the field will continue to grow as teams apply next generation sequencing to additional tumor types. "There are lots of clues pointing to the role of chromatin modeling as being a large factor in an increasing large fraction of human tumors," said Jones. "The story is getting bigger, not smaller."
**__Related stories:__*** linkurl:Fewer mutations in kids' cancer;http://www.the-scientist.com/news/display/57866/
[16th December 2010] *linkurl:"Epigenetics" drives phenotype?;http://www.the-scientist.com/blog/display/57224/
[18th March 2010] *linkurl:A new epigenetic cancer;http://www.the-scientist.com/blog/display/55684/
[11th May 2009]