Genetic Cause Identified in Rare Pediatric Brain Tumor
February 01, 2016
Diagnosis and treatment
decisions for a recently recognized type of children’s brain tumor
should be improved by the discovery of the genetic mechanism that causes it,
say researchers who identified the unusual DNA abnormality in angiocentric
Currently there is no
definitive pathological test to help identify this rare type of low-grade
glioma. Named for their curious behavior of “hugging” blood vessels in the
brain, angiocentric gliomas are usually cured with surgery and don’t need
further treatment with radiation or chemotherapy. But given their recent
description and difficulties in identifying them confidently, some patients
receive the additional therapy, which often is damaging to the growing brain,
in an effort to prevent a recurrence.
“Now we know these
angiocentric gliomas have a different biology, and we have an exact way of
identifying them so that patients can avoid this additional therapy that has
life-long consequences,” said Rameen Beroukhim, MD, PhD, of Dana-Farber Cancer Institute, a senior author of
the report in Nature Genetics along with Keith Ligon, MD, PhD,
and Adam Resnick, PhD. Ligon is a pathologist at Dana-Farber/Boston
Children’s Hospital Cancer and Blood Disorders Center and Dana-Farber/Brigham
and Women’s Cancer Center (DF/BWCC). Resnick is an investigator at Children’s
Hospital of Philadelphia.
Angiocentric gliomas were
recognized as distinct entities less than 10 years ago. Their name reflects the
tumor cells’ tendency to line up around blood vessels. Fewer than 30 cases have
been described in medical literature. Seizures are typically the first symptom
leading to diagnosis. Although they are classified as a tumor, they are not
malignant and don’t spread to other parts of the body.
These rare tumors fall under
the umbrella of pediatric low-grade gliomas (PLGG), which collectively are the most common
pediatric brain tumor. Until now, no specific genetic abnormality had been
identified as a “driver” of angiocentric gliomas.
In the current study, the
researchers analyzed data from 249 PLGG tumors, including 19 angiocentric
gliomas, and discovered an unusual genetic accident as the fundamental cause of
the angiocentric gliomas. The culprit event is a shuffling of DNA segments
that brings together two separate genes, MYB and QKI, which
become joined, or fused. MYB is a “proto-oncogene” – a normal gene that
can become a cancer-causing oncogene. QKI is a tumor-suppressor
gene that normally functions to prevent cells from becoming malignant.
When these two genes are
abnormally joined, the researchers found, it triggers not one but three
different mechanisms that converge to produce a tumor:
control elements called enhancers are “hijacked” and brought closer to the MYB
gene, which increases MYB activity.
- The MYB-QKI fusion
gene causes cells to make a protein that binds to another control element – a
promoter – that also revs up MYB activity, prodding the cells into
- The rearrangement
also knocks out one of the two copies of the QPI tumor suppressor gene,
enabling cancer-related genes to escape control and contribute to tumor
“This represents the first
example of a single driver rearrangement simultaneously transforming cells via
three genetic and epigenetic mechanisms in a cancer,” the authors wrote. They
identified this specific abnormality as “a defining event” found only in the
angiocentric gliomas – it was not present in any of the other pediatric
low-grade gliomas examined in the study.
Because of these findings,
the researchers said, angiocentric glioma should be classified as a separate
biologic entity, with the presence of the gene fusion confirming the diagnosis.
“This could aid in distinguishing angiocentric glioma from tumors with higher
potential for recurrence that could require further treatment,” they said. The
authors have developed the first genetic test now available for these patients
through collaboration with cytogeneticist Azra H. Ligon, PhD, of DF/BWCC.
The research was supported by
A Kids’ Brain Tumor Cure Foundation Pediatric Low-Grade Astrocytoma Foundation
and National Institutes of Health grants R01NS085336 and PO1CA142536.