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2018 ; 13
(7
): e0200343
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PIK3CA mutations are specifically localized to lymphatic endothelial cells of
lymphatic malformations
#MMPMID29985963
Blesinger H
; Kaulfuß S
; Aung T
; Schwoch S
; Prantl L
; Rößler J
; Wilting J
; Becker J
PLoS One
2018[]; 13
(7
): e0200343
PMID29985963
show ga
Lymphatic malformations (LM) are characterized by the overgrowth of lymphatic
vessels during pre- and postnatal development. Macrocystic, microcystic and
combined forms of LM are known. The cysts are lined by lymphatic endothelial
cells (LECs). Resection and sclerotherapy are the most common treatment methods.
Recent studies performed on LM specimens in the United States of America have
identified activating mutations in the phosphatidylinositol-4,5-bisphosphate
3-kinase catalytic subunit alpha (PIK3CA) gene in LM. However, whole tissue but
not isolated cell types were studied. Here, we studied LM tissues resected at the
University Hospitals Freiburg and Regensburg, Germany. We isolated LECs and
fibroblasts separately, and sequenced the commonly affected exons 8, 10, and 21
of the PIK3CA gene. We confirm typical monoallelic mutations in 4 out of 6
LM-derived LEC lines, and describe two new mutations i.) in exon 10 (c.1636C>A;
p.Gln546Lys), and ii.) a 3bp in-frame deletion of GAA (Glu109del). LM-derived
fibroblasts did not possess such mutations, showing cell-type specificity of the
gene defect. High activity of the PIK3CA-AKT- mTOR pathway was demonstrated by
hyperphosphorylation of AKT-Ser473 in all LM-derived LECs (including the ones
with newly identified mutations), as compared to normal LECs. Additionally,
hyperphosphorylation of ERK was seen in all LM-derived LECs, except for the one
with Glu109del. In vitro, the small molecule kinase inhibitors
Buparlisib/BKM-120, Wortmannin, and Ly294002, (all inhibitors of PIK3CA), CAL-101
(inhibitor of PIK3CD), MK-2206 (AKT inhibitor), Sorafenib (multiple kinases
inhibitor), and rapamycin (mTOR inhibitor) significantly blocked proliferation of
LM-derived LECs in a concentration-dependent manner, but also blocked
proliferation of normal LECs. However, MK-2206 appeared to be more specific for
mutated LECs, except in case of Glu109 deletion. In sum, children that are, or
will be, treated with kinase inhibitors must be monitored closely.
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