lo 1 . PcG genes driving cancer

Which EZH2 mutations were identified in follicular and diffuse large B-cell lymphoma?

Recurrent somatic mutations in the SET domain of EZH2 at Tyr641 (Y641)

Are EZH2 hotspot mutations in lymphoma heterozygous or homozygous?

Heterozygous

Do EZH2 hotspot mutations act as gain-of-function or loss-of-function?

Gain-of-function (dominant)

What effect do EZH2 Y641 and A677 mutations have on H3K27me3 levels?

Elevated H3K27me3 levels

What effect do EZH2 Y641 and A677 mutations have on H3K27me2 levels?

Reduced H3K27me2 levels

What is the primary substrate of wild-type EZH2?

H3K27me0

What substrates do Y641 and A677 mutant EZH2 use more efficiently?

H3K27me1 and H3K27me2

What percentage of follicular lymphoma patients have EZH2 mutations?

More than 25% (27% in the study)

Are EZH2 mutations an early or late event in lymphoma?

Early/founding event

What happens when EZH2 Y641F mutant is expressed in mouse B-cells?

Drives lymphoma at high penetrance

What genetic events cooperate with EZH2 mutations to enhance lymphoma?

BCL2 overexpression and p53 loss

In which cancer does EZH2 act as a tumour suppressor?

T-cell acute lymphoblastic leukemia (T-ALL)

What type of EZH2 mutations are found in T-ALL?

Frameshift or nonsense mutations (loss-of-function)

Which other PRC2 complex members are tumour suppressors in T-ALL?

EED and SUZ12

What cancer type shows recurrent EED and SUZ12 loss?

Malignant Peripheral Nerve Sheath Tumours (MPNST)

What effect do EED and SUZ12 mutations have on H3K27me3?

Reduction in H3K27me3 levels

What do EED and SUZ12 mutations disrupt?

PRC2 complex assem