19. Genetics of myelodysplastic syndromes

Question 1

What 4 factors characterise MDS?

Answer 1

1. Clonal expansion of myeloid cells in BM
2. Impaired differentiation, morphology & maturation
3. Cytopenia due to ineffective haematopoiesis & dysplasia
4. Risk of transformation to AML

Question 2

Which cell lineages can be involved in MDS?

Answer 2

All 3 myeloid lineages - erythrocytic, granulocytic, megakryocytic

Question 3

Why is MDS considered pre-malignant?

Answer 3

Some patients acquire additional abnormalities & progress to AML

Question 4

What are the two types of MDS and their causes?

Answer 4

Primary MDS - spontaneous, cause unknown

t-MDS - caused by chemotherapy

Question 5

What proportion of MDS patients have a clonal chromosomal abnormality?

Answer 5

50% - key prognostic marker

Question 6

What are the most common genetic abnormalities seen in MDS?

Answer 6

Copy number changes in all/part of chr 5, 7, 8, 20

Question 7

What is the most common abnormality involving chr 5?

Answer 7

5q- syndrome

Question 8

Name one of the genes involved in 5q- syndrome and its role

Answer 8

Haploinsufficiency for RPS14 - contributes to abnormal erythroid differentiation and apoptosis

Question 9

What is the prognosis associated with 5q- syndrome?

Answer 9

Long survival when is an isolated finding

Low risk of transformation to AML

Question 10

What follow up testing is recommended in 5q- syndrome patients & why?

Answer 10

TP53 testing - mutations predict poor response to Lenolidomide with del(5q)

Question 11

What is the most common abnormality involving chr 7?

Answer 11

Monosomy 7 or 7q-

Question 12

What is the prognosis of monosomy 7 or 7q-?

Answer 12

Poor prognosis

Question 13

What is the only recurrent amplification in MDS?

Answer 13

+8

Question 14

What is the most common abnormality involving chr 20?

What is the risk of progression?

Answer 14

20q-

Low risk of progression to AML

Question 15

Name 2 genes implicated in both ALL and MDS and how

Answer 15

KMT2A/MLL involved in many translocations, most commonly t(9;11), t(11;19), t(11;16)

ETV6 lost in MDS (12p-)

Question 16

What defines a complex karyoytype and what is the risk/prognosis?

Answer 16

More than 3 abnormalities

High risk

Question 17

What are the 5 functional categories of mutated genes in MDS?

Answer 17

1. Spliceosomal
2. Epigenetic modifiers
3. Cohesins
4. TFs (RUNX1, ETV6)
5. Signalling molecules (NF1, NRAS, JAK2, FLT3)

Question 18

Give an example of a gene with a direct association with a specific MDS phenotype / morphology

Answer 18

SF3B1 mutations associated with refractory anaemia with ring sideroblasts (RARS)

Question 19

What causes MDS patients to progress to AML?

Answer 19

Acquisition of an additional driver mutation resulting in proliferation of a subclonal population unable to mature and differentiate normally

Question 20

What is CHIP?

Answer 20

Clonal haematopoiesis of indeterminate potential

Haematopoietic tissue has detectable (>2%) somatic clonal driver mutations in genes associated with haematologic neoplasia but patients do not meet definitive diagnostic criteria for haematologic malignancy

Question 21

What is the advantage of using SNP arrays in MDS testing?

Answer 21

Detect acquired UPD and CN-LOH - commonly seen in MDS