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1348 Part X: Malignant Myeloid Diseases Chapter 87: Myelodysplastic Syndromes 1349

the CDR, and ASXL1, 121,122 which lies outside the CDR and is mutated in to that of patients with noncomplex karyotypes, whereas those with a
a large fraction of MDS patients with or without del(20q). Patients with TP53 mutation have a significantly shorter overall survival. Patients
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del(20q) appear more likely to have thrombocytopenia and are enriched with complex karyotypes on average have fewer mutations in genes
in mutations of the splicing factor gene U2AF1. 123,124 other than TP53.
Loss of Y The isolated loss of the Y chromosome is a rare recur-
rent abnormality observed in just over 2 percent of males with MDS. Somatic Mutations
Like the del(20q) abnormality, –Y is associated with the same cytoge- Acquired mutations of individual genes are significantly more com-
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netic risk as patients with normal karyotypes. It has been argued that mon than karyotypic abnormalities in patients with MDS. Chromo-
–Y is not a pathogenic lesion in MDS, but instead an age-related event somal rearrangements detected by standard cytogenetic techniqes are
that can occur in men without cytopenias. 125,126 However, the presence present in just under 50 percent of cases and more sensitive techniques
of –Y as a somatic change is indicative of oligoclonal, if not monoclonal with greater resolution can uncover small scale or copy number neu-
hematopoiesis and is therefore consistent with the diagnosis of MDS tral abnormalities in an additional 25 percent. However, recurrent
in a cytopenic patient. The larger the –Y clone, the more likely that mutations of single genes can be identified in more than 80 percent of
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evidence of an underlying neoplasm like MDS will be found. Other patients with MDS using targeted sequencing techniques and are likely
genetic abnormalities, including mutations in ten-eleven translocation 2 to be found in all cases studied with whole-genome approaches. Unlike
(TET2) and DNMT3A have also been identified in elderly patients with- most chromosomal abnormalities that span large regions of the genome
out cytopenias or other evidence of hematologic disease, yet these are containing many candidate disease genes, most recurrent mutations
considered pathogenic lesions in MDS. It is unclear if cytopenic patients affect the coding sequence of single genes, identifying them and their
with these markers of clonality, such as –Y, and insufficient evidence for associated molecular pathways as pathogenic drivers. As of this writ-
an MDS diagnosis have comparable prognoses to patients with MDS. ing, there are more than 50 genes known to be recurrently mutated in
Chromosome 17 Abnormalities Including del(17p) A small patients with MDS. A handful of these genes are mutated in a signifi-
fraction of MDS patients will have an abnormality of chromosome 17, cant fraction of cases (10 to 35 percent) with several others in the 5 to
typically in the context of a complex karyotype. The TP53 gene is 10 percent range. But the majority of recurrently mutated genes are
located on 17p13.1 in a region that is recurrently deleted in those rare found only rarely, encompassing fewer than 5 percent and, generally,
patients with either del(17p) or monosomy 17. One copy of 17p is typ- less than 1 percent of cases. In some instances, these rare mutations
ically retained in these cases suggesting that total loss of this region is occur in genes, like the splicing factors U2AF2 or SF1 that are in the
not tolerated. However, the TP53 gene on the remaining chromosome same family as more commonly mutated genes. In other cases, the
is often mutated leaving no wild-type protein. Patients with chromo- infrequently mutated genes, like GNAS and GNB1, represent their own
some 17 abnormalities typically have a poor prognosis, particularly in molecular pathways suggesting that clonal myelodysplasia is a pheno-
the presence of a TP53 mutation. The 17p region can be effectively lost typic manifestation that can be caused by a variety of pathogenic mech-
in patients with an isochromosome 17p abnormality [i(17q)], occurring anisms. The large number of potentially mutated genes and multitude
in just under 1 percent of cases. While these lesions predict a high rate of ways in which they can be combined result in a staggering number
of leukemic transformation, they are rarely associated with a coexisting of possible genetic profiles. The apparent cooperativity between some
TP53 mutation. Instead, they are often found to cooccur with muta- lesions and the mutual exclusivity of other limits this variability to some
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tions of SETBP1, abnormalities that are found more often in patients extent, but still allows for tremendous complexity at the genetic level. As
with both dysplastic and proliferative disease features. 129 a determinant of disease phenotypes, this variation likely explains much
Complex and Monosomal Karyotypes MDS karyotypes can be of the clinical heterogeneity seen in patients with MDS. 137
defined by the number of abnormalities present instead of focusing on Not all somatic mutations have equal pathogenic or clinical signif-
the specific regions involved. Complex karyotypes are defined as having icance. Any patient with clonal hematopoiesis will harbor a large num-
three or more cytogenetic abnormalities of any sort and are strongly ber of acquired mutations throughout their genome. The vast majority
associated with an adverse prognosis. In the International Prognosis of these are incidental mutations acquired over the lifetime of the par-
Scoring System-Revised (IPSS-R), complex karyotypes are further sep- ticular stem cell that eventually grew to clonally dominate hematopoie-
arated in those with exactly three abnormalities and those with four or sis, most of which occurred prior to its expansion. These preceding
more, with the latter group having the highest associated disease risk. mutations are not related to the development of disease and are dis-
Monosomal karyotypes are defined as the loss of two or more entire tributed randomly, typically in noncoding and nonconserved areas of
chromosomes or the deletion of a single chromosome and the presence the genome, suggesting that they have no positive or negative selective
of another structural cytogenetic abnormality. Monosomal karyotypes significance. Collectively, these nonrecurrent mutations without patho-
are not necessarily complex and complex karyotypes are not necessar- genic significance are described as passenger mutations because their
ily monosomal, but in practice, there is substantial overlap between the presence in the expanded clone is only because they happen to coexist
two. The most frequent abnormalities seen in both monosomal and with much rarer driver mutations, responsible for the clonal outgrowth
complex karyotypes involve chromosomes 5 and 7. The IPSS-R con- and the eventual development of disease. Driver mutations are typi-
siders complex, but not monosomal karyotype as an independent risk cally recurrent and predicted to have pathogenic consequences like the
factor and there has been ambiguity about whether complex versus alteration of a protein coding sequence or changes in the expression of
monosomal karyotypes are better predictors of disease risk. 130–133 one or more disease-related genes. Driver mutations can be early trans-
Approximately 50 percent of patients with complex karyotypes formative events, in which case they would be found in every subse-
have a concomitant TP53 mutation and account for the majority of quent disease cell derived from that clone, or they can be late events,
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patients with mutations of this gene. The incidence of TP53 muta- often associated with progressive disease. Some genes, like splicing fac-
tion is particularly high when the complex karyotype includes del(5q) tors, are predominantly mutated early and are typically found as part of
as an associated abnormality. 90,92,135 The adverse prognostic significance the dominant disease clone. Other genes, like NRAS and SETBP1, are
associated with complex karyotypes may be largely driven by their fre- typically secondary mutations acquired later in the disease course and
quent association with TP53 mutations. 134,136 Complex karyotype MDS are often found as emergent subclones that may expand in size during
patients with intact TP53 have a median overall survival comparable progression. 90,138,139

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