19. Genetics of myelodysplastic syndromes Flashcards
What 4 factors characterise MDS?
- Clonal expansion of myeloid cells in BM
- Impaired differentiation, morphology & maturation
- Cytopenia due to ineffective haematopoiesis & dysplasia
- Risk of transformation to AML
Which cell lineages can be involved in MDS?
All 3 myeloid lineages - erythrocytic, granulocytic, megakryocytic
Why is MDS considered pre-malignant?
Some patients acquire additional abnormalities & progress to AML
What are the two types of MDS and their causes?
Primary MDS - spontaneous, cause unknown
t-MDS - caused by chemotherapy
What proportion of MDS patients have a clonal chromosomal abnormality?
50% - key prognostic marker
What are the most common genetic abnormalities seen in MDS?
Copy number changes in all/part of chr 5, 7, 8, 20
What is the most common abnormality involving chr 5?
5q- syndrome
Name one of the genes involved in 5q- syndrome and its role
Haploinsufficiency for RPS14 - contributes to abnormal erythroid differentiation and apoptosis
What is the prognosis associated with 5q- syndrome?
Long survival when is an isolated finding
Low risk of transformation to AML
What follow up testing is recommended in 5q- syndrome patients & why?
TP53 testing - mutations predict poor response to Lenolidomide with del(5q)
What is the most common abnormality involving chr 7?
Monosomy 7 or 7q-
What is the prognosis of monosomy 7 or 7q-?
Poor prognosis
What is the only recurrent amplification in MDS?
+8
What is the most common abnormality involving chr 20?
What is the risk of progression?
20q-
Low risk of progression to AML
Name 2 genes implicated in both ALL and MDS and how
KMT2A/MLL involved in many translocations, most commonly t(9;11), t(11;19), t(11;16)
ETV6 lost in MDS (12p-)
What defines a complex karyoytype and what is the risk/prognosis?
More than 3 abnormalities
High risk
What are the 5 functional categories of mutated genes in MDS?
- Spliceosomal
- Epigenetic modifiers
- Cohesins
- TFs (RUNX1, ETV6)
- Signalling molecules (NF1, NRAS, JAK2, FLT3)
Give an example of a gene with a direct association with a specific MDS phenotype / morphology
SF3B1 mutations associated with refractory anaemia with ring sideroblasts (RARS)
What causes MDS patients to progress to AML?
Acquisition of an additional driver mutation resulting in proliferation of a subclonal population unable to mature and differentiate normally
What is CHIP?
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
What is the advantage of using SNP arrays in MDS testing?
Detect acquired UPD and CN-LOH - commonly seen in MDS
