May create opportunities for new, less aggressive therapies for
children with subset of brain tumors
LOS ANGELES–(BUSINESS WIRE)–A multi-institutional group of researchers, led by investigators at
Children’s Hospital Los Angeles and the University of Michigan, have
identified a simple and inexpensive tool for assessing the prognosis of
pediatric brain tumors called ependymomas. Their study, which
demonstrates the epigenetic mechanism behind these tumors, may offer
future opportunities for novel therapeutic options. It is published
online by Science Translational Medicine.
Childhood posterior fossa (PF) ependymomas are tumors found largely in
the hind brain (consisting of the cerebellum, pons and the brainstem) of
children. Routine assessment of tumor grade and other markers in PF
ependymomas do not correlate well with outcomes in these tumors,
highlighting the need for new prognostic markers. Genomic sequencing
efforts have not identified mutations in these tumors, and the origin of
PF ependymomas remains obscure.
While lacking recurrent genetic mutations, a subset of these tumors
exhibits alterations in DNA methylation. In this study, the researchers
looked at modification of histones – protein components of the chromatin
around which DNA winds, and which play a role in gene regulation – in
particular, histone H3.
Co-lead investigator Sriram Venneti, MD, PhD, of the Department of
Pathology at the University of Michigan, observed that histone H3 is
modified differently in pediatric posterior fossa ependymoma.
Specifically, 80 percent of these tumors exhibited loss of the H3K27me3,
a repressive mark, while 20 percent of tumors retained H3K27me3.
Researchers went back and looked at MRIs and outcomes of children
treated for these tumors and identified that tumors with loss of
H3K27me3 behaved more aggressively and showed poor overall survival.
This suggests that reduced H3K27me3 may be a prognostic indicator in PF
“Detection of H3K27me3 by immunohistochemical staining is a widely
available and cost-effective surrogate molecular marker. This test can
be readily implemented in most departments of pathology and provides a
much-needed tool to risk stratify and identify ependymoma patients who
would potentially benefit from epigenetic therapies,” said co-lead
investigator Alexander R. Judkins, MD, of the Department of Pathology
and Laboratory Medicine at CHLA and Keck School of Medicine of the
University of Southern California.
This loss in H3K27me3, along with other epigenetic changes, was similar
to that observed in another type of pediatric brain tumor of the hind
brain region termed diffuse intrinsic pontine gliomas (DIPGs). This
suggests that both of these tumors arise from similar epigenetic states.
Intriguingly, researchers found that certain progenitor cells in this
part of the brain also showed low H3K27me3, suggesting – as both tumors
share epigenetic similarities – that low methylation of H3K27me3 is
important to the development of tumors in this region of the brain.
According to the Collaborative Ependymoma Research Network (CERN)
Foundation, the current standard therapy for ependymomas includes total
surgery that may be followed by radiation therapy. Complete surgical
resection is often not possible due to tumor location and concerns about
damaging the surrounding brain during surgery.
Because such treatment can come with a cognitive cost, especially to
pediatric patients, there has been a lot of interest in what drives
ependymomas so that they may be treated more effectively. “By
demonstrating the epigenetic mechanism – that we theorize likely goes
awry during brain development – we will be better able to identify these
tumors, determine a more accurate prognosis and – importantly – perhaps
develop better therapeutic options,” said Venneti.
Additional contributors include Jill Bayliss, Chan Chung, Pooja
Panwalkar, Abhijit Parolia, Arul M. Chinnaiyanm, Richard C. McEachin and
Marcin Cieslik, University of Michigan; Piali Mukherjee and Ari Melnick,
Weill Medical College of Cornell University; Chao Lu, C. David Allis and
Benjamin Sabari, The Rockefeller University; Siddhant U. Jain and Peter
W. Lewis, University of Wisconsin-Madison; Daniel Martinez, Children’s
Hospital of Philadelphia; Ashley S. Margol and Benita Tamrazi,
Children’s Hospital Los Angeles; Melike Pekmezci, UC San Francisco;
Benjamin A. Garcia, Perelman School of Medicine, University of
Pennsylvania; Gaspare La Rocca and Craig B. Thompson, Memorial Sloan
Kettering Cancer Center; Mariarita Santi, Children’s Hospital of
Philadelphia; and Cynthia Hawkins, The Hospital for Sick Children,
This work was supported by grants from the National Cancer Institute of
the NIH (K08 CA181475), the Mathew Larson Foundation, the Sidney Kimmel
Foundation and the Doris Duke Foundation (SV); and RO1GM110174 and
P01CA196539 (BAG). RCM is supported by the University of Michigan
Bioinformatics Core. C.L. is the Kandarian Family Fellow supported by
the Damon Runyon Cancer Research Foundation (DRG-2195-14). CBT is
supported by the Cancer Center Support Grant (CCSG) of Memorial Sloan
Kettering Cancer Center (CBT) – a NIH P30 CA008748.
Children’s Hospital Los Angeles
Debra Kain, 323-361-7628