Genes related to Down syndrome abnormalities may protect against solid
tumors

Date:
August 6, 2020
Source:
Ann & Robert H. Lurie Children's Hospital of Chicago
Summary:
Scientists have discovered that a set of genes with decreased
expression in individuals with Down syndrome may lead to clinical
abnormalities in this population, such as poor muscle development
and heart valve problems. Impairment in these same genes may also
protect people with Down syndrome from developing solid tumors.



FULL STORY ========================================================================== Scientists from Stanley Manne Children's Research Institute at Ann &
Robert H.

Lurie Children's Hospital of Chicago discovered that a set of genes
with decreased expression in individuals with Down syndrome may lead to clinical abnormalities in this population, such as poor muscle development
and heart valve problems. Impairment in these same genes may also protect people with Down syndrome from developing solid tumors. Their findings
were published in Scientific Reports.


==========================================================================
"Our promising preliminary data carries strong potential for ultimately developing gene-targeted therapies to inhibit solid tumor growth in the
general population," says co-lead author Yekaterina Galat, BS, Research Associate at the Manne Research Institute at Lurie Children's. "Our
findings may also provide gene targets for therapies aimed at alleviating
the clinical abnormalities in people with Down syndrome." Down syndrome
is a congenital genetic disorder that is associated with cognitive
impairment, reduced muscle tone, heart defects, and other clinical
anomalies. At the same time, individuals with Down syndrome have lower prevalence of solid tumor formation.

The study used skin samples from two patients with Down syndrome to
create induced pluripotent stem cells that were then differentiated into endothelial cells, which build blood vessels and the vascular system, and mesodermal cells, which are responsible for connective tissues and muscle development. During the process of differentiation, in the progenitor
phase, Manne Research Institute scientists discovered down-regulated
genes that appear to be involved in the abnormal muscle development and
heart problems that are common in people with Down syndrome.

By studying the role of these genes in biochemical pathways relevant
to solid tumor development, they found that the decreased expression of
such genes interferes with the processes needed for solid tumor formation
and growth.

These genes produced impeded cell movement, slower proliferation and
reduced inflammatory response -- creating a microenvironment that is
not conducive to solid tumors. Genome-wide analyses was then performed
to confirm these findings, using publicly available data from 11,000
patients.

"When we performed genomic analyses comparing mesodermal and endothelial
cell lines, we were surprised to find that trisomy 21 impacted gene
expression across the entire genome. Furthermore, the decreased expression
of the genes we studied was consistent, and the large extent of their down-regulation was notable as well," says co-lead author Mariana
Perepitchka, BA, Research Associate at the Manne Research Institute at
Lurie Children's. "This significant down-regulation potentially creates conditions that are opposite of what solid tumors would need to take
hold. So in a way, Down syndrome provides us with a non-traditional lens
to study cancer development." "We still need to validate our findings in
an animal model," says senior author Vasil Galat, PhD, Director of Human
iPS and Stem Cell Core at Manne Research Institute at Lurie Children's
and Research Assistant Professor of Pathology at Northwestern University Feinberg School of Medicine. "The potential for gene- targeted therapies
is very exciting, especially since it could help individuals born with
Down syndrome and the general population battling cancer."

========================================================================== Story Source: Materials provided by Ann_&_Robert_H._Lurie_Children's_Hospital_of_Chicago.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Yekaterina Galat, Mariana Perepitchka, Irina Elcheva, Stephen
Iannaccone,
Philip M. Iannaccone, Vasiliy Galat. iPSC-derived progenitor
stromal cells provide new insights into aberrant musculoskeletal
development and resistance to cancer in down syndrome. Scientific
Reports, 2020; 10 (1) DOI: 10.1038/s41598-020-69418-9 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200806092427.htm

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