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Correlation of myelodysplastic syndromes with i(17)(q10) and TP 53 and SETBP 1 mutations

2015; Wiley; Volume: 171; Issue: 1 Linguagem: Inglês

10.1111/bjh.13355

1365-2141

Vera Ademà, María José Larráyoz, Marı́a José Calasanz, Laura Palomo, Ana Patiño-Garcı́a, Xabier Agirre, Jesús María Hernández‐Rivas, Eva Lumbreras, Ismael Buño, Carolina Martínez‐Laperche, Mar Mallo, Olga García, Sara Álvarez, Beatriz Segovia Blázquez, José Cervera, Elisa Luño, Alberto Valiente, María T. Vallespí, Leonor Arenillas, Rosa Collado, Jaime Pérez de Oteyza, Françesc Solé,

Lymphoma Diagnosis and Treatment

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders that are highly prevalent in the elderly. Isochromosome 17(q10) [i(17q)] has a frequency of 0·4–0·8%, and cytogenetic risk stratification suggests that isolated i(17q) is of intermediate prognostic significance (Brunning et al, 2008; Greenberg et al, 2012; Schanz et al, 2012). It has been postulated that i(17q) may be associated with TP53 mutations, although a recent study found no association (Kanagal-Shamanna et al, 2012). SETBP1 is located at 18q21.1 and mutations of this gene have been reported in several haematological malignancies (Cristóbal et al, 2010; Fernandez-Mercado et al, 2013; Piazza et al, 2013). We investigated the mutational status of TP53 and SETBP1 in 27 untreated MDS patients (who provided written informed consent) reported to the Spanish MDS group, as TP53 mutations and i(17q) have been shown to rarely co-exist in recent reports of concurrent i(17q) and SETBP1 mutations. Patients were classified according to the World Health Organization 2008 criteria (Brunning et al, 2008) and G-banding karyotypes were described according to the International System for Human Cytogenetic Nomenclature 2009 (Shaffer et al, 2009) (Table 1). Genomic DNA was isolated from cells fixed in Carnoy's fixative and from fresh bone marrow samples (QIAamp DNA mini-kit, Qiagen Inc, Valencia, CA, USA). TP53 exons 5–9 and SETBP1 exon 3 were amplified and sequenced as previously described (Meggendorfer et al, 2013). Patients were divided into three groups: no mutations, TP53 mutations and SETBP1 mutations. Statistical analyses (spss 22.0. SPSS Inc., Chicago, IL, USA) were performed for these three groups and for the overall patient population. Baseline characteristics and main clinical variables were compared by Kruskal–Wallis and Pearson or Fisher's exact test for continuous or categorical variables, respectively. Overall survival (OS) was measured from haematological diagnosis to death from any cause or last follow-up. Survival curves were plotted according to the Kaplan–Meier method, and compared using the log-rank test. Univariate and multivariate analyses of OS were performed using the Cox proportional hazard ratio (HR) model. Two-sided P values A) at the splicing recognition site. SETBP1 was analysed in all patients. Eleven (41%) had SETBP1 non-synonymous point mutations (mainly located in residues 868–871). Five of 11 (45%) had heterozygous mutations in D868N. Four of these patients had isolated i(17q); the remaining one had i(17q) with one additional abnormality. SETBP1 heterozygous G870S mutations (27%) were found in 3/11 patients, all with isolated i(17q). The three remaining patients had single heterozygous mutations in D868Y, S869G and I871T [D868Y patient had a CK, while the others presented isolated i(17q)]. A statistically significant relationship was found between mutation group and karyotype classification (P = 0·009). Most TP53 mutated cases (80%) presented a CK, meanwhile 82% of SETBP1 mutations presented isolated i(17q). There were no statistically significant differences between the groups regarding haemoglobin, leucocytes, platelets, polymorphonuclear cells, absolute neutrophil count or blast percentage. The TP53-mutated group showed worse OS than non-mutated and SETBP1-mutated groups {median OS [95% confidence interval (CI)]: 2·9 (2·4, 3·5), 14·1 (0, 33·7) and 13·9 (7·9, 19·8), respectively, P = 0·001}. Patients with a CK showed worse OS than isolated i(17q) and i(17q) with one additional abnormality [median OS (95% CI): 3·8 (2·5, 5·1), 26·5 (7·2, 45·8) and 21·3 (8·3, 34·3), respectively, P < 0·001] (Figure S1). Univariate analysis of OS (Table 2) revealed a statistically significant difference between non-mutated and TP53-mutated patients [HR (95% CI): 0·07 (0·01, 0·3); P = 0·002], and between SETBP1-mutated and TP53-mutated patients [HR (95% CI): 0·11 (0·02, 0·5); P = 0·006]. There were also significant differences between the cytogenetic groups: isolated i(17q) versus CK [HR (95% CI): 0·07 (0·02, 0·3); P < 0·001]and i(17q) with an additional abnormality versus CK [HR (95% CI): 0·07 (0·01, 0·3); P = 0·001]. In multivariate analysis (Table 2), and because of the high correlation between karyotype and mutation type, only the karyotype remained as a prognostic factor, considering CK as the reference category: isolated i(17q) versus CK (P = 0·002), and i(17q) with an additional abnormality versus CK (P = 0·01). 0·07 (0·01–0·3) P = 0·002 0·109 (0·02–0·5) P = 0·006 0·07 (0·02–0·3) P < 0·001 0·09 (0·02–0·4) P = 0·002 0·07 (0·01–0·3) P = 0·001 0·104 (0·02–0·6) P = 0·01 Fifteen patients evolved to acute myeloid leukaemia (AML) (seven with no mutations, five with SETBP1 mutations, three with TP53 mutations), but AML evolution did not differ significantly between the study groups. A relationship between SETBP1 and MDS has been established in numerous studies. A recent whole-exome sequencing (WES) study in atypical chronic myeloid leukaemia detected two cases with a novel SETBP1 mutation (Piazza et al, 2013), while Makishima et al (2013) identified new recurrent somatic SETBP1 mutations when carrying out WES in myeloid malignancies. Of particular note is a study in which a significant association was observed between SETBP1 mutation and i(17q) (Meggendorfer et al, 2013). In our study, 41% (11/27) of patients with i(17q) presented with SETBP1 mutations; ten of these patients had isolated i(17q). These findings are consistent with Meggendorfer et al (2013), who reported isolated i(17q) and SETBP1 mutations in 19/35 MDS patients (54%) and, also regarding the mutual exclusivity of SETBP1 and TP53 mutations, none of the patients in our series had co-existing SETBP1 and TP53 mutations. Makishima et al (2013) suggested a poor prognosis for patients with SETBP1 mutations. However, their study did not focus on MDS cases with i(17q), and most of the patients presented monosomy 7. Their findings suggest that the poor prognosis is related to the presence of monosomy 7, rather than SETBP1 status. In summary, patients with i(17q) presented with infrequent TP53 mutations and a high incidence of SETBP1 mutations. Patients with isolated i(17q) presented with a significantly higher rate of SETBP1 mutations than TP53 mutations, whereas patients with CKs presented with a higher incidence of TP53 mutations. Our findings suggest that, in MDS patients with isolated i(17q) or i(17q) plus one additional abnormality, a better informed and more accurate prognosis can be achieved by studying the mutational status of SETBP1 or, where SETBP1 mutations are absent, by analysing TP53. This work was supported in part by Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Spain (PI 11/02010 and PI 14/00013); Red Temática de Investigación Cooperativa en Cáncer (RTICC, FEDER) (RD12/0036/0044, RD12/0036/0014); Plataforma Nacional de Biobancos (PT13/0010/0026); 2014 SGR225 (GRE) Generalitat de Catalunya; Fundación Española de Hematología y Hemoterapia (FEHH); Fundació Internacional Josep Carreras, Obra Social "la Caixa"; and Celgene Spain. Editorial support was provided by Sandra Lee Lewis of the Investigator Initiated Research Writing Group, part of KnowledgePoint360, an Ash field company, and was funded by Celgene Corporation. Collection and assembly of data: Vera Adema, María José Larráyoz, María José Calasanz, Laura Palomo, Ana Patiño-García, Xabier Agirre, Jesús María Hernández-Rivas, Eva Lumbreras, Ismael Buño, Carolina Martinez-Laperche, Mar Mallo, Olga García, Sara Álvarez, Beatriz Blazquez, José Cervera, Elisa Luño, Alberto Valiente, María Teresa Vallespí, Leonor Arenillas, Rosa Collado, Jaime Pérez-Oteyza and Francesc Solé. Data analysis and interpretation: Vera Adema, María José Larráyoz, María José Calasanz, Olga García and Francesc Solé. Manuscript writing: All authors. Final approval of manuscript: all authors. All the authors have read the ICMJE disclosure form and declare that they have no conflicts of interest to disclose. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.