Northumbria academic, Dr Jill McKay, Associate
Professor of Molecular Epidemiology in the department of Applied Sciences, has
been part of a groundbreaking study published in the journal Molecular Cancer that
has uncovered molecular markers in blood at birth that are linked to later
development of acute lymphoblastic leukaemia (ALL), the most common cancer type
that affects children. These markers were also present in cancerous tissues
from children with leukaemia, and they served as indicators of patient
survival. This research offers new hope for early diagnosis and potential
therapeutic interventions in childhood cancer, which is the leading cause of
death among diseases in children.
The new study, which was led by scientists from the
International Agency for Research on Cancer (IARC) in collaboration with
Northumbria University and 16 other partner institutions worldwide, used an
innovative approach to trace the molecular origins of cancer back to birth. The
researchers profiled molecular maps in patients at various stages: birth,
diagnosis, remission, and recurrence. At the core of these maps is the
epigenome, which intricately weaves DNA strands into a molecular imprint of
nature and nurture: what our genes provide, and how the environment influences
them. This allows the epigenome to capture a molecular snapshot – a kind of
diary – of early-life factors that the baby was exposed to during pregnancy.
“This study is the result of a large-scale multidisciplinary
effort, substantial investment, and extensive international collaboration,”
says Dr Zdenko Herceg, Head of the Epigenomics and Mechanisms Branch at IARC
and co-senior author of the study. “By combining epidemiology, clinical
oncology, and advanced laboratory science, we have gained unique insights into
the causes of cancer and identified biomarkers that could lead to early
detection and personalized risk stratification and therapy.”
To generate epigenetic imprints, biological samples are
required. However, most paediatric cancer research has relied on clinical
samples collected after disease onset. This raises concerns of reverse
causality, where biological processes identified in this way may result from
the cancer rather than being its cause.
To address this, the scientists searched for epigenetic (DNA
methylation) markers in both surrogate (blood) and cancerous tissues across the
course of leukaemia development, starting at the time of birth by using
archived Guthrie cards (or cord blood, when available) from the children.
Guthrie cards harbour blood spots, often originating from baby heel pricks, and
are commonly collected as part of routine neonatal screenings. This uncovered
potential epigenetic precursors of leukaemia detectable at birth, before the
disease manifests.
Dr McKay supplied key data from a UK study based
in the North East of England which helped to prove the stability of the
epigenetic marks in historically collected Guthrie card samples: “Our previous
research provided evidence that blood spot samples collected around birth
remained stable over time and was not related to the year of collection, thus
allowing for a reliable identification of the makers present when they were
analysed more than 30+ years later.
The fact that the archived samples can be depended upon for
analysing DNA methylation the biomarker of interest in this study, regardless
of how long they have been stored, was crucial, as it proved our methodologies
were sound. If this was not the case, then that child’s likelihood of
developing leukaemia could not be reliably predicted based upon the measurement
of these biomarkers.”
After the patients were followed up for more than 10 years,
the findings revealed that specific DNA methylation alterations at birth can
serve as significant biomarkers for ALL development, prognosis, and survival.
In the absence of changes in the DNA code, methylation levels are potentially
reversible, and this is what was observed in patients who responded positively
to therapy. The findings of this research were reproducible with different
technologies, in three continents, and in two ethnicities, including the
often-underrepresented Hispanic ethnicity; Hispanic children have the highest
rates of childhood leukaemia worldwide.
“Because childhood cancer may have origins in utero, we have
essentially travelled back in time to collect blood samples at birth from
children who later developed cancer,” says IARC scientist Dr Akram Ghantous,
the lead author of the study. “We are mapping the molecular ‘diaries’ of nature
and nurture in patients with cancer while tracing these diaries back to birth –
in a way, reversing the arrow of time to uncover early origins of the disease.”
With further validation, these findings could revolutionise
early detection and treatment of childhood leukaemia. Future research will
expand to larger, more diverse populations to uncover additional molecular
precursors of paediatric ALL and enhance clinical applications.
