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1346 Part X: Malignant Myeloid Diseases Chapter 87: Myelodysplastic Syndromes 1347

TABLE 87–2. Recurrently Mutated Myelodysplastic Syndrome Genes
Mutated Gene Frequency in MDS (%) Prognostic Value Additional Information
SF3B1 20–30 Favorable Strongly associated with ring sideroblasts
Splicing SRSF2 10–15 Adverse More frequent in CMML
8–12
U2AF1
Adverse
Associated with del(20q)
ZRSR2 5–10 ?
TET2 20–25 Neutral More frequent in CMML
Epigenetic regulators IDH1/IDH2 <5 ? Adverse More frequent in CMML
DNMT3A
Adverse
12–18
15–25
ASXL1
5–10
More frequent in CMML
Adverse
EZH2
ATRX
<2
KMD6A <2 ? ? Associated with ATMDS
RUNX1 10–15 Adverse Familial in rare cases
Transcription ETV6 <5 Adverse Rarely translocated in MDS
?
GATA2
<2
Commonly familial, rarely somatic
PHF6
<2
?
TP53 8–12 Adverse Associated with complex karyotypes
STAG2 5–10 ?
Cohesins RAD21 <5 ? ?
<2
SMC3
SMC1A <2 ?
NRAS/KRAS 5–10 Adverse More frequent in CMML
Signaling JAK2 <5 Neutral Enriched in RARS-t
CBL/CBLB
More frequent in CMML
<5
Adverse
PTPN11 <2 Adverse More frequent in JMML, can be germline
GNAS/GNB1 <2 ? G-protein signalling pathway
BRCC3 <2 ? DNA repair pathway
Others PIGA <2 ? ? Cause of PNH clones

<2
Can be germline
TERT/TERC
FANC genes <2 ? Typically germline
ATMDS, acquired thalassemia and myelodysplastic syndrome; CMML, chronic myelomonocytic leukemia; JMML, juvenile myelomonocytic leu-
kemia; MDS, myelodysplastic syndrome; PNH, paroxysmal nocturnal hemoglobinuria; RARS-t, refractory anemia with ringed sideroblasts and
thrombocytosis.

progression of MDS. Many of these lesions are associated with particu- likelihood that multiple gene losses cooperate to generate a disease-
73
lar clinical phenotypes, including differences in disease manifestation, related phenotype. However, MDS-related chromosomal abnormal-
response to therapy, risk of AML transformation and overall survival. ities do have important clinical significance. For example, they can
However, the use of genetic features to classify disease subtypes or per- establish the presence of clonal hematopoiesis and in the appropriate
sonalize the care of individual patients is still rudimentary. context, can serve as presumptive evidence of MDS. Chromosomal
abnormalities are key elements in the determination of prognosis and
Cytogenetics in the case of del(5q), can predict response to a particular treatment.
Chromosomal amplifications and translocations are relatively rare Del(5q) Deletion of the long arm of chromosome 5 is the most
events in MDS compared with other hematologic malignancies. The common karyotypic abnormality observed in MDS, occurring in
most frequent chromosomal abnormalities seen in MDS, present in 15 percent of cases, half of which have several other karyotype abnor-
nearly half of all cases, are deletions of chromosomal segments or loss malities. Studies examining the breakpoints of deletions across multiple
of entire chromosomes (monosomies). Several such lesions are recur- patients have identified two commonly deleted regions (CDRs), one on
rent and typically involve commonly deleted regions that are presumed 5q31.1 and the other at 5q32–33.3. Patients with del(5q) often have dele-
to harbor one or more tumor-suppressor genes. Identifying individ- tions that encompass both CDRs and can include proximal and distal
ual gene drivers from these regions has been challenging because of chromosomal regions as well. Larger deletions that include more proxi-
the large amount of genomic territory that they encompass and the mal genes, like APC, and more distal genes, like NPM1, are much more

Kaushansky_chapter 87_p1341-1372.indd 1346 9/21/15 11:05 AM