**6. Genetics**

Novel genomic tools are now available that can both confirm clonality and provide valuable prognostic information (**Figure 4**).

#### **Figure 4.**

*Most frequently mutated pathways: serial acquisition of somaticmutations causes clonal stem cell expansion and impaired differentiation.*

**123**

*Cytogenetic and Genetic Advances in Myelodysplasia Syndromes*

tions including coding exons and copy number alterations [17, 18].

It is crucial to the understanding of the pathogenesis and disease phenotypes of MDS to decipher the mutations that are involved in the positive selection ("driver" mutations) and the mechanisms by which those mutations are positively selected. Next-generation sequencing (NGS) has revealed a landscape of genetic altera-

The most common genetic alterations in MDS are mutations affecting RNA splicing and epigenetic modifier pathways. Those mutations are found on MDS more than AML, They are implicated on pathogenesis of MDS rather than

Mutations are frequently associated with specific disease phenotype, drug response, and clinical outcomes, and thus, it is essential to be familiar with MDS

MDS is characterised by a lot of recurrent mutation genes and diversify of affected pathways. However, myeloid driver mutations have common fundamental biological property: they all can be responsible of clonal dominance at the stem

The diversity of clinical MDS phenotypes associated with specific mutations may be attributable to differential correlation of the hematopoietic stem cell HSC

More than 90% of MDS have somatic mutations, those mutations identify molecular pathways that drive the pathogenesis of MDS. Even low abundance mutations can have prognostic value as they identify emerging clones before they impact

Among major mutational targets in MDS are the molecules involved in DNA

NGS using whole-exome sequencing showed that MDS patients carry a median of 9 somatic mutations in the entire coding region, those mutations include driver mutations that advance clonal selection and passenger mutations (random muta-

If we focus on the most reccurent mutated pathways, 65% of MDS patients harboured mutations in RNA splicing (SF3B1, SRSF2, U2AF1, ZRSR2) [12], followed by 47% harbouring mutations touching DNA methylation genes (DNMT3A, IDH1/2, TET2) and 28% in histone modification genes (ASXL1,BCOR, EZH2)

Recurrent mutations are described in genes regulating DNA methylation (DNMT3A, TET2, IDH1/2), and post-translational chromatin modification (EZH2, ASXL1). Also transcription regulation (TP53, RUNX1, GATA2), are found, such as

MDS and primary AML share common mutational targets, pleading for the same pathogenesis in different neoplasms. However, the recurrence of these mutations differed between MDS and primary AML; in MDS overrepresentation of mutations in splicing factors (SFs) and epigenetic regulators are often reported, in contrast of AML, genetic abnormalities include mutations in receptor tyrosine kinases like FLT3, RAS pathway genes, and CEBPA and IDH1/2, witch are the most frequent

methylations, chromatin modification, RNA splicing, transcription, signal

Many insights have been done about the implication of these mutations on RNA splicing and the epigenome, and initial murine models of several of these mutations

MDS is typically driven by a multistep genetic process with recurrent mutations affecting basic cellular pathways, including RNA splicing, epigenome regulation, and myeloid transcriptional coordination, those abnormalities caused DNA damage

*DOI: http://dx.doi.org/10.5772/intechopen.97112*

genetics for better management of patients.

and provoked stress responses, and growth factor signalling.

self-renewal program and lineage-specific differentiation programs.

transduction, cohesion regulation, and DNA repair.

tions) that do not promote disease [20].

primary AML.

cell level.

clinical parameters.

**Figure 3** [21–23].

mutations reported [24].

have been reported [19].

*Cytogenetic and Genetic Advances in Myelodysplasia Syndromes DOI: http://dx.doi.org/10.5772/intechopen.97112*

*Cytogenetics - Classical and Molecular Strategies for Analysing Heredity Material*

(q11;p11); t(Y;1)(q12;q12), der(16) t(1;16)(q11;q11).

interstitial, with loss of material between band p11 and p13.

del(13q) witch are recurrent in MDS.

massive parallel sequencing itself [16].

provide valuable prognostic information (**Figure 4**).

**6. Genetics**

particularly presentation involving frequent thrombocytopenia.

• del(20q) which is not considered as specific of MDS, but has been related to a

• Recurrent unbalanced translocations involving 1q have been identified in primary MDS with a partial trisomy for the long arm of chromosome 1: t(1;15)

• secondary MDS are charactherized by translocation associated with the long arm of chromosome 7, we can also found: Deletion 9q, del(11q), del(12p) and

• deletion of short arm of chromosome 12, del(12p) are variable. It can be associated with multiple karyotypic changes in sMDS. De novo disorders are rare with and 12p- chromosome as a sole aberration is rarely seen. Deletions are

• Acquired monosomy X can be sporadically found in female MDS patients. Xq13 may also be involved in translocations in MDS, as well as in rearrangements such as an isodicentric chromosome X with breakpoint at q13 (idic (X)(q13))

Thus, chromosomal aberrations still have clinical relevance in MDS even in the era of genomic medicine. Because they basically consist in copy number changes, their detection will likely be improved by array-based karyotyping and/or by

Novel genomic tools are now available that can both confirm clonality and

*Most frequently mutated pathways: serial acquisition of somaticmutations causes clonal stem cell expansion* 

**122**

**Figure 4.**

*and impaired differentiation.*

It is crucial to the understanding of the pathogenesis and disease phenotypes of MDS to decipher the mutations that are involved in the positive selection ("driver" mutations) and the mechanisms by which those mutations are positively selected.

Next-generation sequencing (NGS) has revealed a landscape of genetic alterations including coding exons and copy number alterations [17, 18].

The most common genetic alterations in MDS are mutations affecting RNA splicing and epigenetic modifier pathways. Those mutations are found on MDS more than AML, They are implicated on pathogenesis of MDS rather than primary AML.

Many insights have been done about the implication of these mutations on RNA splicing and the epigenome, and initial murine models of several of these mutations have been reported [19].

Mutations are frequently associated with specific disease phenotype, drug response, and clinical outcomes, and thus, it is essential to be familiar with MDS genetics for better management of patients.

MDS is typically driven by a multistep genetic process with recurrent mutations affecting basic cellular pathways, including RNA splicing, epigenome regulation, and myeloid transcriptional coordination, those abnormalities caused DNA damage and provoked stress responses, and growth factor signalling.

MDS is characterised by a lot of recurrent mutation genes and diversify of affected pathways. However, myeloid driver mutations have common fundamental biological property: they all can be responsible of clonal dominance at the stem cell level.

The diversity of clinical MDS phenotypes associated with specific mutations may be attributable to differential correlation of the hematopoietic stem cell HSC self-renewal program and lineage-specific differentiation programs.

More than 90% of MDS have somatic mutations, those mutations identify molecular pathways that drive the pathogenesis of MDS. Even low abundance mutations can have prognostic value as they identify emerging clones before they impact clinical parameters.

Among major mutational targets in MDS are the molecules involved in DNA methylations, chromatin modification, RNA splicing, transcription, signal transduction, cohesion regulation, and DNA repair.

NGS using whole-exome sequencing showed that MDS patients carry a median of 9 somatic mutations in the entire coding region, those mutations include driver mutations that advance clonal selection and passenger mutations (random mutations) that do not promote disease [20].

If we focus on the most reccurent mutated pathways, 65% of MDS patients harboured mutations in RNA splicing (SF3B1, SRSF2, U2AF1, ZRSR2) [12], followed by 47% harbouring mutations touching DNA methylation genes (DNMT3A, IDH1/2, TET2) and 28% in histone modification genes (ASXL1,BCOR, EZH2) **Figure 3** [21–23].

MDS and primary AML share common mutational targets, pleading for the same pathogenesis in different neoplasms. However, the recurrence of these mutations differed between MDS and primary AML; in MDS overrepresentation of mutations in splicing factors (SFs) and epigenetic regulators are often reported, in contrast of AML, genetic abnormalities include mutations in receptor tyrosine kinases like FLT3, RAS pathway genes, and CEBPA and IDH1/2, witch are the most frequent mutations reported [24].

Recurrent mutations are described in genes regulating DNA methylation (DNMT3A, TET2, IDH1/2), and post-translational chromatin modification (EZH2, ASXL1). Also transcription regulation (TP53, RUNX1, GATA2), are found, such as

the RNA spliceosome machinery (SF3B1, U2AF1, SRSF2, ZRSR2), cohesion complexes (STAG2), and signal transduction (JAK2, KRAS, CBL) [21].

Mutations in TP53, EZH2, ETV6, RUNX1, SRSF2 and ASXL1 occurs low survivals. [24] These mutations can predict responses treatment by hypomethylating agents and allogeneic HSCT.

Furthermore, internal tandem duplication of FLT3 (FLT3 -ITD), have been described during MDS progression and represent potential therapeutic targets [25, 26].

Therefore, a better knowledge of the molecular landscape in MDS has crucial role for determination of implications on treatment response, prognostication, and novel molecular therapeutic targeting.

Mutations in isocitrate dehydrogenase 1 or 2 (IDH1 and IDH2) are important to identify at the time of diagnosis of high- or very high-risk MDS. These particular mutations lead to abnormal leukemogenesis. Mutated IDH1 or IDH2 are not common and are only found in approximately 4–12% of patients with MDS. Those gene mutations have treatment impact. Recently, two IDH inhibitors, specifically ivosidenib targeting IDH1 and enasidenib for IDH2, are approved by the United States Food and Drug Administration (FDA) for use in AML, but not in MDS [27, 28].

Both agents are undergoing investigation in combination with azacitidine or with induction chemotherapy in patients with IDH-mutant MDS.

Other mutations are very important to identify early because of their prognostic impact, like SF3B1 mutations, in fact mutations of SF3B1 are strongly associated with ring sederoblasts, and a typical SF3B1 can be presumptive evidence of MDS, and have more favorable prognosis [29].

More than third of MDS patients with less than 5% of blasts will have an adverse gene mutation. These include mutations cited before like SRSF2, U2AF1, ASXL1, RUNX1, EZH1, TP53, IDH1, NRAS, and PRPF8, but the only mutation having good prognosis is SF3B1 mutation [30].

For patient with MDS and having more than 5% of blasts (5–30% blasts), several mutated genes retain their in higher risk MDS. In fact, mutation of TP53, CBL, RUNX1, PRPF8 are utch more common and remain adverse, and SF3B1 mutation are rare end no longer favourable.

Somatic mutations alone are not great predictors of outcomes after treatment with approved MDS therapies, but mutations of TP53 and epigenic regulators like TET2 and DNMT3A have shown associations with response to hypomethylating drugs in some studies. In contrast of that, we do have a cytogenical marker there is very good for predictive response to therapy: it s about Del (5q) and lenalidomide. In fact patient having Del(5q) can response favourably to lenalidomide, if TP53 mutations are absents, because TP53 mutations indicate resistance to lenalidomide and predict relapse or progression even after allogeneic stem cell transplantation.

Data are accumulating to support use of next-generation sequencing (NGS) in the diagnosis and management of patients with MDS.

The treatment and management of older patients with MDS is extremely challenging due to a number of reasons, including advanced disease, intolerability to therapy, significant comorbidities, and potential for more drug–drug interactions with concomitant therapy.

#### **7. Conclusion**

Our knowledge about the genetics of myelodysplastic syndromes (MDS) and related myeloid disorders has been dramatically improved during the past decade, in which revolutionized sequencing technologies have played a major role.

**125**

**Author details**

Mounia Bendari1

\* and Nisrine Khoubila<sup>2</sup>

\*Address all correspondence to: bendarimounia@gmail.com

provided the original work is properly cited.

1 Mohammed VI University of Health Sciences, Casablanca, Morocco

2 Faculty of Medicine and Pharmacy of Casablanca, Hassan II University, Morocco

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Cytogenetic and Genetic Advances in Myelodysplasia Syndromes*

condition with a clearly elucidated molecular mechanism.

Cytogenetic abnormalities have extensive utility in MDS, they have many implications for diagnosis and prognosis. The best example is represented by MDS with isolated del(5q). the presence of del(5q) is known to be a lenalidomide-responsive

The use of additional genomic information, provided by DNA microarrays and sequencing, holds great promise in further refining the classification and manage-

At present, NGS is rarely incorporated into clinical guidelines although an increasing number of studies have demonstrated the benefit of using NGS in the

*DOI: http://dx.doi.org/10.5772/intechopen.97112*

clinical management of MDS patients [31].

Authors declare have no conflict of interest.

ment of these disorders.

**Conflict of interest**

*Cytogenetic and Genetic Advances in Myelodysplasia Syndromes DOI: http://dx.doi.org/10.5772/intechopen.97112*

Cytogenetic abnormalities have extensive utility in MDS, they have many implications for diagnosis and prognosis. The best example is represented by MDS with isolated del(5q). the presence of del(5q) is known to be a lenalidomide-responsive condition with a clearly elucidated molecular mechanism.

The use of additional genomic information, provided by DNA microarrays and sequencing, holds great promise in further refining the classification and management of these disorders.

At present, NGS is rarely incorporated into clinical guidelines although an increasing number of studies have demonstrated the benefit of using NGS in the clinical management of MDS patients [31].
