Researchers mine data and connect the dots about processes driving neuroblastoma

Date:
October 14, 2020
Source:
St. Jude Children's Research Hospital
Summary:
Scientists lead genome analysis to better understand one of the
most common childhood solid tumors.



FULL STORY ========================================================================== Researchers have used insight from a comprehensive genomic analysis of neuroblastoma to learn about the process driving one of the most common childhood solid tumors. The findings revealed possible approaches for developing precision medicines to improve patient outcomes. St. Jude
Children's Research Hospital scientists led the study, which appears
today in the journal Nature Communications.


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The analysis involved whole genome, whole exome and whole transcriptome sequencing of 702 neuroblastoma samples. The tumors included 23 samples
from patients who relapsed. The work identified associations among common mutational traits that researchers hope to exploit therapeutically.

"This combined analysis of a large cohort of tumors provided insight into previously unrecognized correlations at work in neuroblastoma as well as
the discovery of less common driver mutations," said corresponding author Jinghui Zhang, Ph.D., chair of the St. Jude Department of Computational Biology.

The co-corresponding authors are Michael Dyer, Ph.D., chair of the
St. Jude Department of Developmental Neurobiology and a Howard Hughes
Medical Institute investigator, and Michael Hogarty, M.D., of the
Children's Hospital of Philadelphia.

Connecting the dots between common mutations and oxidative stress
Researchers used a common mutational pattern almost like a fingerprint
to identify internal processes fueling the tumor's growth and spread.

Investigators knew DNA-damaging molecules called reactive oxygen species
and oxidative stress are elevated in neuroblastoma. Reactive oxygen
species are generated in the mitochondria of cells. The analysis found an association between a chromosomal mutation in 65% of neuroblastomas and
the DNA-damaging molecules. These tumors have an extra piece of chromosome
17. That piece includes genes expressed in the mitochondria. The results suggest that mitochondrial gene defects may lead to increased production
of reactive oxygen species, fueling tumor growth and drug resistance.



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A St. Jude Cloud search of more than 1,000 pediatric tumor genomes from 39 cancer types found the association was not unique. Researchers reported
that more than 20% of samples from another cancer, rhabdomyosarcoma, had increased expression of mitochondrial genes and a pattern of increased oxidative stress.

The finding strengthened the newly identified connection between
mitochondrial gene defects and the mutational process.

"Thanks to this analysis, we have a deeper understanding of
the alterations driving neuroblastoma, including how tumors form,
progress and respond to therapy," Dyer said. "That is the foundation
for translational research going forward." Neuroblastoma predictors Neuroblastoma develops in fetal nerve cells called neuroblasts that fail
to mature normally. While 7 to 10% of childhood cancers are neuroblastoma,
the tumor accounts for half of all cancers in infants. This cancer
generally begins in the adrenal glands, but it can also start in the
chest, the spine or spinal cord regions, abdomen and other areas.

Treatment and outcomes vary widely based on patient age. Survival rates
for the youngest patients (younger than 18 months old) are about 95%. For older, high- risk patients, survival rates are only about 50%.



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This study reinforced the association between patient age and the
mutations driving the disease. For example, the genes MYCN and TERT were commonly altered in patients 3.8 years of age or younger while mutations
in ATRX were more frequent in children with a median age of 5.6 years.

MYCN, ATRX and a "beautiful convergence" The analysis offered insight
into previous research from Dyer and his colleagues. The researchers
noted that while MYCN or ATRX were potent drivers of neuroblastoma,
the mutations did not occur together.

"In most cancers, you would expect to find patients with both mutations
who did even worse," Dyer said. "But we never found this combination,
which was a surprise." Dyer said this analysis suggests why. MYCN and
ATRX mutations induce oxidative stress. Dyer hypothesized that, when
combined, the mutations may be lethal to tumor cells.

"This was a beautiful convergence of two different approaches to
understanding the mutational processes underway inside cells," he said.

Recurring, but less common gene alterations The analysis included data
from St.

Jude, including the St. Jude-Washington University Pediatric Cancer Genome Project; the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, managed by the National Cancer Institute;
and the Children's Oncology Group, a clinical cooperative trials group.

The large number of samples aided efforts to find recurring, but less
common neuroblastoma alterations that may be candidates for precision medicines. The newly identified mutations were in the genes FGFR1 and ALK.


========================================================================== Story Source: Materials provided by
St._Jude_Children's_Research_Hospital. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Samuel W. Brady, Yanling Liu, Xiaotu Ma, Alexander M. Gout, Kohei
Hagiwara, Xin Zhou, Jian Wang, Michael Macias, Xiaolong Chen, John
Easton, Heather L. Mulder, Michael Rusch, Lu Wang, Joy Nakitandwe,
Shaohua Lei, Eric M. Davis, Arlene Naranjo, Cheng Cheng, John
M. Maris, James R. Downing, Nai-Kong V. Cheung, Michael D. Hogarty,
Michael A.

Dyer, Jinghui Zhang. Pan-neuroblastoma analysis reveals age- and
signature-associated driver alterations. Nature Communications,
2020; 11 (1) DOI: 10.1038/s41467-020-18987-4 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201014171334.htm

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