Genetic changes in non-coding DNA impacts
outcomes
PHILADELPHIA and MEMPHIS, Tenn., Aug. 14,
2024 /PRNewswire/ -- Researchers at Children's
Hospital of Philadelphia (CHOP),
St. Jude Children's Research Hospital (St. Jude) and the
Children's Oncology Group (COG) today announced a significant
paradigm shift in the understanding of T-lineage acute
lymphoblastic leukemia (T-ALL), an aggressive and high-risk form of
cancer, to one frequently driven by genetic changes in non-coding
portions of our DNA. The collaborative study, supported by the
Gabriella Miller Kids First Pediatric Research Program (Kids First)
and National Institutes of Health (NIH) Common Fund, was
published today in the journal Nature.
Many children, adolescents, and young adult patients with T-ALL
traditionally respond well to initial treatment. However, patients
who relapse or have treatment-resistant disease often face a dire
prognosis. Given the aggressive nature and rapid progression of the
disease, and limited understanding of the genetic basis of T-ALL,
researchers saw an urgent need for new and effective approaches to
diagnosis and treatment.
"This paper is the first to transcend previous barriers and
comprehensively profile the whole genome, uncovering critical
insights in more than 1,300 children, adolescents and young adults
with T-ALL," said David T. Teachey,
M.D., an attending physician, Director of Clinical Research at
the Center for Childhood Cancer Research at CHOP and
Chair of the Acute Lymphoblastic Leukemia disease committee in the
COG. "These findings are a significant clinical advancement, as the
goal in treating T-ALL is to prevent relapse, which requires
identifying the patients most at risk. This data now makes it
possible to risk stratify patients with T-cell leukemia,
identifying those with a high-risk of relapsing so we can treat
them with newer or alternative medicines."
Prior studies were unable to identify important genetic changes
in T-ALL, as they focused on the coding genome, the part of
DNA that encodes proteins, the building blocks of cells. However,
only 1% of DNA is coding, while the other 99% is termed
non-coding.
Once considered useless, scientists now recognize that the
non-coding region plays a key role in regulating biological
processes. It signals the cell when to produce certain proteins,
like a crossing guard aiding people to safely cross the street.
In this case, researchers studied more than 1,300 patients
treated on the COG AALL0434 clinical trial and sequenced both the
tumor and non-tumor genomes of each patient. While the researchers
previously suspected that non-coding DNA in T-ALL played an
important role, this study's findings are the first ever to
establish that at a large scale.
The study found that approximately 60% of the genetic changes
driving T-ALL cancer cells are non-coding changes. This
fundamentally alters the way researchers think about T-ALL,
offering a better understanding of disease biology. This leads to
innovative treatments, including new immunotherapies developed at
CHOP and St. Jude.
Traditionally, patients with T-ALL have been categorized by
risk based on their therapy response and immunophenotype, which
profiles cell surface proteins as part of the diagnostic workup.
While cell surface protein expression helps define T-ALL subtypes,
it hasn't proven effective in consistently identifying which
patients have a good prognosis. The new comprehensive data revealed
why, strongly suggesting that a genomic approach replace the
current immunophenotypic classification. As a result, the
researchers developed models that incorporate genetics and response
to treatment to risk stratify patients with T-ALL accurately and
are currently in the process of validating results using patient
samples from the next COG trial of T-ALL.
"It was striking how abundant these non-coding changes were and
how many of them were enhancer perturbation events, whether it was
hijacking or co-option of an existing enhancer, or changes that
generated a new enhancer," said Charles Mullighan, MBBS, MD, St.
Jude Children's Research Hospital, Comprehensive Cancer Center
deputy director and Department of Pathology member. "We now have a
much stronger framework to take these alterations back to the lab
and say now we've got better information to build the right models
to understand the biology, and then to test therapy. We have very
clear information that these are the sorts of alterations that
people need to focus on to build a diagnostic test."
Researchers were able to classify T-ALL into 15 subtypes with
distinct gene expression and genomic drivers, including previously
undefined subtypes. They refined the classification of known
subtypes and showed that driver lesions, other genetic changes, and
the original cell type work together to define the genomic subtype
and the clinical and biological characteristics of a condition.
They also observed a significant link between the type of gene
alterations and outcomes in T-ALL. This new observation shows it is
not only which gene is altered in the cancer cells, but also how it
is altered, that helps define prognosis and chance of a cure.
"Future research must continue to determine broader applications
for this approach," said Teachey. "These findings offer a strong a
roadmap for improving patient outcomes and curing more children and
adults with T-ALL."
In addition to the Gabriella Miller Kids First Pediatric
Research Program and National Institutes of Health (NIH) Common
Fund, the study was supported by the Leukemia and Lymphoma Society,
Alex's Lemonade Stand Foundation, Hyundai Hope on Wheels, the COG
Foundation, ALSAC, the fundraising and awareness organization of
St. Jude, and private donations from patients and families,
including the Harrison Willing
Memorial Research Fund, the Invisible Prince Foundation, and the
Aiden Everett Davies Innovation Fund.
Polonen, et al. "The genomic basis of childhood T-lineage acute
lymphoblastic leukemia." Nature. Online August 14, 2024.
DOI:10.1038/s41586-024-07807-0.
About Children's Hospital of Philadelphia:
A non-profit, charitable organization, Children's Hospital of
Philadelphia was founded in 1855
as the nation's first pediatric hospital. Through its long-standing
commitment to providing exceptional patient care, training new
generations of pediatric healthcare professionals, and pioneering
major research initiatives, the hospital has fostered many
discoveries that have benefited children worldwide. Its pediatric
research program is among the largest in the country. The
institution has a well-established history of providing advanced
pediatric care close to home through its CHOP Care Network, which
includes more than 50 primary care practices, specialty care and
surgical centers, urgent care centers, and community hospital
alliances throughout Pennsylvania
and New Jersey, as well as the
Middleman Family Pavilion and its dedicated pediatric
emergency department in King of
Prussia. In addition, its unique family-centered care and
public service programs have brought Children's Hospital of
Philadelphia recognition as a
leading advocate for children and adolescents. For more
information, visit https://www.chop.edu.
About St. Jude Children's Research Hospital
St. Jude
Children's Research Hospital is leading the way the world
understands, treats and cures childhood cancer, sickle cell disease
and other life-threatening disorders. It is the only National
Cancer Institute-designated Comprehensive Cancer Center devoted
solely to children. Treatments developed at St.
Jude have helped push the overall childhood cancer survival
rate from 20% to 80% since the hospital opened more than 60 years
ago. St. Jude shares the breakthroughs it makes to help
doctors and researchers at local hospitals and cancer centers
around the world improve the quality of treatment and care for even
more children. To learn more,
visit stjude.org, read St. Jude Progress, a
digital magazine,
[https://www.stjude.org/research/progress.html] and follow St.
Jude on social media at @stjuderesearch.
Contact: Jennifer Lee
Children's Hospital of Philadelphia
(267) 426-6084
leej41@chop.edu
Contact: Gary Bridgman
St. Jude Children's Research Hospital
Desk: (901) 595-2028
gary.bridgman@stjude.org
media@stjude.org
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