Table 1 Recurring genomic and proteomic alterations in diffuse midline glioma.

ACVR1

R206H, G328V, G328W

H3.1K27M, EZHIP

32%

Pons, thalamus

LDN212854

[27, 46, 92, 93]

Activin receptor type-1 (ACVR1)

ATM

G2342V, L2877F

H3.3K27M, EZHIP

6%

Pons

AZD1390

[27, 43, 94]

ND

ATRX

H2254R, R2197L, L1357fs

H3.3K27M, EZHIP

10%

Pons, thalamus

Pyridostatin

[27, 49, 93]

ND

BCOR

C1363fs, A535V, G101fs

H3.1K27M, EZHIP

8%

Pons

[27, 93,94,95]

ND

BCORL1

S425I, R21H

H3.1K27M, H3.3K27M

7%

Pons

[1, 95]

ND

CCND1/2/3

Amplification

H3.3K27M

15%

Pons, thalamus

Palbociclib, ribociclib, abemaciclib

[43]

G1/S-specific cyclin-D2 (CCND2) / Cyclin-dependent kinases 4 and 6 (CDK4, CDK6)

CDK4/6

Amplification, L185V

H3.3K27M

15%

Pons

Palbociclib, ribociclib, abemaciclib

[1]

G1/S-specific cyclin-D2 (CCND2) / Cyclin-dependent kinases 4 and 6 (CDK4, CDK6)

DDX11

R186W, R167T

H3.3K27M

6%

Pons

Irinotecan

[49]

ND

EGFR

R108K, Amplification, CNG

H3.1K27M, H3.3K27M, EZHIP

4%

Pons, thalamus

Gefitinib, erlotinib

[1, 5, 14, 49, 96]

ND

FGFR1

K697E, N98S, N546K, K656E

H3.3K27M, H3.1K27M, EZHIP

12.5%

Pons, thalamus, midbrain

AZ4547, dovatinib, PD173074, ponatinib

[27, 93, 97]

ND

GNAQ

T96S

H3.3K27M

6%

Pons

Tris DBA palladium

[49]

ND

IGF2R

K162R, D1830E

H3.1K27M

8%

Pons

GSK1838705A

[68]

ND

KDM6A

Deletion, CNL

H3.3K27M

6%

Pons

[49, 94]

ND

KDR

S1154P, Amplification, CNG

H3.3K27M

4.8%

Pons

Mebendazole

[1, 49, 98]

ND

KIT

T96P, Amplification, CNG

H3.3K27M

4.8%

Pons

Mebendazole

[1, 49, 98]

ND

KMT5B

R187*, M646fs

H3.3K27M, EZHIP

1%

Pons

Olaparib, talazoparib

[6]

ND

MET

P664P, Amplification

H3.3K27M

10%

Pons, midbrain

Cabozantinib

[5, 49]

ND

MTOR

A1971V

H3.3K27M

1%

Pons

Everolimus, fimepinostat, AZD2014

[1, 55, 99]

Phosphatidylinositol-4,5-bisphosphate 3-kinase signaling cascade (PIK3CA/PIK3R1/PTEN/MTOR)

MYC

R33C, Amplification

H3.3K27M

12%

Pons

Omomyc

[1, 57]

MYC proto-oncogene protein (MYC)/ MYCN proto-oncogene protein (MYCN)

MYCN

Amplification, CNG

EZHIP

8%

Pons

Bromodomain inhibitors

[14, 68]

MYC proto-oncogene protein (MYC)/ MYCN proto-oncogene protein (MYCN)

NF1

G295R, R1204W, Deletion

H3.3K27M

10%

Pons

Binimetinib, trametinib

[1, 14, 95, 99]

ND

NTRK1/2/3

TPM3_NTRK1 VCL_NTRK2 ETV6_NTRK3

H3.3K27M

3.7%

Pons, midbrain

Larotrectinib

[5, 98]

ND

PDGFRA

Y288C, C235Y, Amplification

H3.3K27M

30%

Pons

Crenolanib, dasatinib

[1, 42, 93]

Platelet derived growth factor receptor alpha (PDGFRA)

PIK3CA

E545K, I391M, H1047R

H3.3K27M, H3.1K27M, EZHIP

12%

Pons, thalamus, midbrain

Paxalisib, fimepinostat

[43, 55, 93]

Phosphatidylinositol-4,5-bisphosphate 3-kinase signaling cascade (PIK3CA/PIK3R1/PTEN/MTOR)

PIK3R1

K567E, G376R

H3.3K27M, EZHIP

18%

Pons, thalamus, midbrain

Paxalisib, everolimus, fimepinostat

[27, 43, 49, 55]

Phosphatidylinositol-4,5-bisphosphate 3-kinase signaling cascade (PIK3CA/PIK3R1/PTEN/MTOR)

PPM1D

W427*, E525X, Q404X, E405X, 428 fs

H3.1K27M, H3.3K27M, EZHIP

25%

Pons, thalamus, midbrain

CCT007093, GSK2830371, olaparib

[27, 53, 70]

Protein phosphatase, Mg2+/Mn2+dependent 1D (PPM1D)

PTEN

A126S, R130X, Deletion

H3.1K27M, H3.3K27M, EZHIP

19%

Pons, thalamus

Fimepinostat

[7, 27, 43, 49, 53, 55]

Phosphatidylinositol-4,5-bisphosphate 3-kinase signaling cascade (PIK3CA/PIK3R1/PTEN/MTOR)

RB1

Amplification, Deletion

H3.1K27M, H3.3K27M

16%

Pons, thalamus

[14, 97]

ND

RPTOR

D857N

H3.3K27M

1%

Pons

[1, 43]

ND

TERT

C228T, C250T

H3.3K27M

2%

Pons

Imetelstat

[5]

ND

TOP3A

C633Y

H3.3K27M

3–4%

Pons, midbrain

PIP-199

[1]

ND

TP53

G245S, R175H, R248Q, R248W, R273C, R273H, S241F, V157F

H3.1K27M, H3.3K27M, EZHIP

60–80%

Pons, thalamus, midbrain

APR-246, GSK-J4

[1, 27, 30]

Cellular tumor antigen p53 (TP53)

TSC2

D1587V, Q1035*

EZHIP

2%

Pons

Rapamycin

[1]

ND