acute lymphoblastic leukemia
Image by Hind Medyouf
Breaches in looping chromosomal structures known as insulated neighborhoods can activate oncogenes capable of fueling aggressive tumor growth, according to research published in Science.
These neighborhood breaches were particularly frequent in T-cell acute lymphoblastic leukemia (T-ALL) and esophageal and liver carcinoma.
In some cases, the breaches allowed enhancer elements to activate previously silent oncogenes.
“This new understanding of the role of chromosome structure in cancer gene misregulation reveals the powerful influence of the genome’s structure in human health and disease,” said study author Richard Young, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts.
These findings build on previous work in which Dr Young and his colleagues charted human genome structure and described its influence on gene control in healthy cells.
By mapping the genome’s 3-dimensional conformation, the researchers found that key genes controlling cell identity are found in insulated neighborhoods, whose loops are maintained through anchor sites bound by the protein CTCF.
All essential gene regulation, including the control of proper activation and repression, takes place within these enclosed neighborhoods.
The researchers also found these CTCF loop anchor sites are maintained across various cell types in the human body and are highly conserved in primate genomes. Such widespread structural conservation led the team to hypothesize that disruptions in genome conformation might be associated with disease, including cancers.
Sure enough, subsequent systematic genomic analysis of more than 50 cancer cell types revealed mutations affecting CTCF anchor sites, which led to the loss of insulated neighborhood boundaries.
By mapping insulated neighborhoods in T-ALL, the researchers found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes.
The team also found the genomes of esophageal and liver carcinoma samples were enriched for boundary CTCF site mutations. The genes located in the most frequently mutated neighborhoods included known proto-oncogenes and genes not previously associated with these malignancies.
“We hadn’t known if these types of mutations contributed to cancer,” Dr Young said. “Now, we have multiple examples where these disruptions activate oncogenes that play major roles in tumorigenesis.”
The researchers noted that this oncogenic mechanism may be valuable for identifying genes that drive poorly understood cancers.
“In some cancers, such as esophageal carcinoma, the most frequent genetic mutation occurs at the CTCF sites, which is quite striking,” said Denes Hnisz, PhD, a researcher in the Young lab.
“In addition, there are still many cancers whose driver mutations and oncogenes are not known, and mapping altered structures may reveal the key oncogenes in these cancers.”
In an attempt to confirm the relationship between structural disruption and oncogenesis, the researchers used genome editing techniques to introduce CTCF anchor site deletions in non-malignant cells. They found these mutations were sufficient to activate oncogenes that are silent in normal cells.
The researchers said these findings suggest future mapping of genome structure in individual cancer patients might improve diagnosis and help guide treatment protocols.
“Now that we understand how perturbations in the genome’s structure can contribute to oncogenesis, we’re developing strategies to efficiently diagnose and potentially fix these faulty neighborhoods,” said Abe Weintraub, a graduate student in the Young lab.
