lo 2 . Disruption of PcG function across other cancer types

What histone H3 mutation is found in paediatric glioblastoma?

Lys27Met (K27M) in H3.3 (H3F3A) and H3.1 (HIST3H1B)

How does H3K27M affect global H3K27me3 levels?

Reduces global H3K27me3 levels

How does H3K27M affect H3K27ac levels?

Increases H3K27ac levels

How does H3K27M inhibit PRC2?

Through interaction with the EZH2 subunit

What is the mechanism of H3K27M mutation on PRC2?

Docks PRC2 at target genes, preventing spreading of H3K27me3

What cellular consequence results from H3K27M mutations?

Failure to differentiate down neural lineages (cell-fate blockages)

What gene is upregulated by EZH2 inhibitors in DMG cells?

CDKN2A (INK4A)

What is the main challenge for using EZH2 inhibitors in diffuse midline glioma?

Blood-brain barrier issues in drug delivery

Which PR-DUB complex subunit has germline mutations predisposing to mesothelioma?

BAP1

What cancers are associated with somatic BAP1 mutations?

Pleural mesothelioma, uveal melanoma, and cholangiocarcinoma

Are BAP1 mutations gain-of-function or loss-of-function?

Loss-of-function

What environmental factor is linked to mesothelioma with BAP1 mutations?

High asbestos exposure

What happens when BAP1 heterozygosity is combined with asbestos exposure in mice?

Animals become more sensitive and induce mesothelioma formation

Does BAP1 promote or inhibit PRC2 mediated gene repression?

BAP1 promotes PRC2 mediated gene repression

What effect does BAP1 loss have on H2AK119ub1 and H3K27me3 across the genome?

Causes accumulation of H2AK119ub1 and H3K27me3 across the genome

What type of ASXL1 mutations occur in myeloid malignancies?

Truncating mutations (frameshift or nonsense)

Are ASXL1 mutations heterozygous or homozygous?

Heterozygous

What domain is lacking in truncated ASXL1 proteins?

The C-terminal PHD domain

What malignancies are associated with ASXL1 mutations?

AML, CMML, and MPN (myeloid malignancies)

Do ASXL1 truncations alone induce myeloid malignancies in mice?

Yes, without other cooperative mutations

Have ASXL1 truncations been reported as gain-of-function or loss-of-function?

Some reports suggest gain-of-function

Which SWI/SNF subunit is biallelically inactivated in malignant rhabdoid tumours?

SNF5 (SMARCB1/INI1)

Are SNF5 mutations the sole recurrent event in rhabdoid tumours?

Yes, essentially the sole recurrent event

Do rhabdoid tumours have high or low mutation rates?

Extremely low mutation rates

Is PRC2 activity critical for development of MRT?

Yes, PRC2 activity is criti