Myelodysplastic Syndromes with I(17)(q10) and Prognostic Implications of Mutations of TP53 and SETBP1
Authors: Adema Vera , Maria Jose Larrayoz , Maria Jose Calasanz , Palomo Laura , Patiño-Garcia Ana , Aguirre Xabier , Hernández-Rivas Jesús María , Lumbreras Eva , Buno Ismael , Martínez-Laperche Carolina , Mallo Mar , Garcia Olga , Gomez-Marzo Paula , Alvarez Sara , Blazquez Beatriz , Cervera Jose , Luño Elisa , Valiente Alberto , Vallespi Teresa , Vicente Ana , Arenillas Leonor , Collado Rosa , Perez-Oteyza Jaime , Sole Francesc 
Published: October 2019

Abstract
INTRODUCTION
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal myeloid stem cell disorders highly prevalent in elderly populations. MDS are characterized by inefficient hematopoiesis, peripheral blood (PB) cytopenias, and increased risk of transformation to acute myeloid leukemia (AML; 20–30%). Around 50% of MDS patients carry at least one karyotoypic aberration, the most common being 5q-, -7/7q-, +8, 20q-, and isochromosome 17(q10) [i(17q)]. Isochromosome 17(q10) according to cytogenetic risk stratification is of intermediate prognostic significance when is observed as a single abnormality. As i(17q) has be postulated to be associated to recurrent mutational patterns we investigated the TP53 and SETBP1 mutational status in 31 untreated MDS patients harboring i(17q).
METHODS
Genomic DNA was isolated from fixed cells from bone marrow samples using QIAamp DNA mini-kit Qiagen. TP53 exons 5–9 and SETBP1 exon 3 were amplified using PCR. Amplification products were all purified and sequenced in an automated sequencer. Additionally, we studied the methylation status of TP53 in 21 of the 31 patients. Sequence analyses were performed with PyroQ-CpG analysis software.
RESULTS
SETBP1 mutational spectrum was characterized by the presence of non-synonmous point mutations, mainly located in residues 868-871 in 13 out of the 31 analyzed patients (41.9 %). In seven of the 13 positive cases, the mutations corresponded to heterozygous D868N, in 5 cases associated with an isolated i(17q) and with 1 additional abnormality in the remaining samples. Three of the 13 SETBP1 mutations were heterozygous G870S associated to i(17q) as a single abnormality. Another three patients had single heterozygous mutations S869G, and I871T along with an i(17q) as a single abnormality or D868Y in the context of a complex karyotype. Regarding TP53 mutations six of the 31 had non-synonymous point mutations. Two patients had mutations in exon 7, three had mutations in exons 5, 6, and 8, and one patient had an intronic mutation at the splicing recognition site.
A statistically significant correlation was found between TP53 mutation and a complex karyotype (P=0.001), and between SETBP1 mutation and isolated i(17q) (P=0.001). Univariate analysis for overall survival (OS) found a statistically significant difference between non-mutated and TP53-mutated patients (14.1 months vs. 2.9 months, respectively; P=0.001), and between SETBP1-mutated and TP53-mutated patients (14.5 months vs. 2.9 months, respectively; P=0.002). Only one patient, with isolated i(17q), was found to have an aberrant TP53 methylation status.
CONCLUSIONS
MDS patients with i(17q) as a sole abnormality presented a higher incidence of SETBP1 mutations, whereas a higher incidence of TP53 mutations, were found in the presence of complex karyotypes. These data allowed us to conclude that a better informed and more accurate prognosis can be achieved in MDS patients with isolated i(17q) or i(17q) plus one additional abnormality, by studying the mutational status of SETBP1 as a first approach.
ACKNOWLEDGEMENTS: This work has been partially supported by grants from Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, Spain (PI 11/02010); by Red Temática de Investigación Cooperativa en Cáncer (RTICC, FEDER) (RD07/0020/2004; RD12/0036/0044); 2014 SGR225 (GRE) Generalitat de Catalunya; Fundació Internacional Josep Carreras; Obra Social “la Caixa”; Sociedad Española de Hematología y Hemoterapia (SEHH) and Celgene Spain.

Disclosures
Sole: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.