3.3 Glioma subtypes correlate with respective protein patterns
Although
the heterogeneity of gliomas has
been described in terms of histochemistry and prognosis [2,
4],
the
understanding of low- and high-grade gliomas
remains
rudimentary
to date,
and
there is no effective
diagnostic
method based on proteins
[25,
26].
In
response to the
poor
diagnostic outcomes in different subtypes of gliomas,
we
next focused on resolving protein pattern differences among gliomas.
Firstly,
integrated proteomic analysis of different grades of glioma showed
independent and well-separated
clusters.
Low-grade
gliomas (WHO grade II and III) exhibited a close correlation and
differed
from grade IV gliomas (Figure 4A). Complementarily,
gliosarcoma
(GSM),
a
rare form of grade IV gliomas (2%) that has both
sarcomatous
and malignant glial components [17],
was
found as a relatively separate entity in
principal
component analysis (PCA)
and
even
had a closer relationship with grade III glioma when using
Pearson
correlation
(Figure
S3A and B).
However,
in
GBMs, no
separate
clustering
betweenIDH1 mutation (IV-Mut) and wild type (IV-WT) was observed.
To
compare the proteome differences
between low- and high-grade gliomas, we grouped WHO grades II and III
tumors into a single consolidated low-grade group (II/III-Mut) and
compared it to GBMs with IDH1 mutation (IV-Mut). In total, 36
proteins were aberrantly expressed in IV-Mut versus II/III-Mut (P< 0.05), of which 25 proteins were upregulated and 11 proteins
were downregulated (Figure 4B and Figure S3B and C). Of note, the
downregulated proteins in IV-Mut were associated with poor survival,
whereas upregulated proteins were associated with the immune response.
IDH1/2mutant
GBMs are distinct from wild-type GBMs with respect to molecular and
clinical features, including prognosis [27, 28].
We
next elucidated the proteomic differences between IV-Mut and IV-WT GBMs,
which
accounted
for
66
upregulated proteins and 10 downregulated proteins
(Figure
S3E).
To
further investigate these
differentially
expressed proteins (DEPs),
gene
set enrichment analysis (GSEA) was performed (Figure 4C).
Tumor
invasion-related
processes
(e.g., Rho GTPase cycle,
cellular
amino acid metabolic process, membrane trafficking, and ferroptosis)
were predominately upregulated in
IV-Mut.
Intriguingly,
ferroptosis,
a newly discovered form of cell death, is not only
correlated
with cell migration but also represents a better prognosis in IV-Mut
versus IV-WT [29,
30].