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Myelodysplastic syndrome

Impact of somatic mutations in myelodysplastic patients with isolated partial or total loss of chromosome 7

Abstract

Monosomy 7 [−7] and/or partial loss of chromosome 7 [del(7q)] are associated with poor and intermediate prognosis, respectively, in myelodysplastic syndromes (MDS), but somatic mutations may also play a key complementary role. We analyzed the impact on the outcomes of deep targeted mutational screening in 280 MDS patients with −7/del(7q) as isolated cytogenetic abnormality (86 with del(7q) and 194 with −7). Patients with del(7q) or −7 had similar demographic and disease-related characteristics. Somatic mutations were detected in 79% (93/117) of patients (82% in −7 and 73% in del(7q) group). Median number of mutations per patient was 2 (range 0–8). There was no difference in mutation frequency between the two groups. Patients harbouring ≥2 mutations had a worse outcome than patients with <2 or no mutations (leukaemic transformation at 24 months, 38% and 20%, respectively, p = 0.044). Untreated patients with del(7q) had better overall survival (OS) compared with −7 (median OS, 34 vs 17 months, p = 0.034). In multivariable analysis, blast count, TP53 mutations and number of mutations were independent predictors of OS, whereas the cytogenetic subgroups did not retain prognostic relevance. This study highlights the importance of mutational analysis in terms of prognosis in MDS patients with isolated −7 or del(7q).

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Fig. 1
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Fig. 4: Overall survival according to chromosome 7 abnormality.
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Fig. 6: Cumulative incidence (CI) of AML and death by mutation number.

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Funding

This work was supported in part by a grant from the Instituto de Salud Carlos III, Ministerio de Economia y Competividad, Spain (PI/14/00013; PI/17/0575); 2017 SGR288 (GRC) Generalitat de Catalunya; economical support from CERCA Programme/Generalitat de Catalunya, Fundació Internacional Josep Carreras and from Celgene International. The research leading to this invention has received funding from ‘la Caixa’ Foundation.

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GJM designed the study and provided funding for the research; EC and AGK performed the research and the statistical analysis; EC and AGK collected data, analyzed data and wrote the paper; EC, AGK, VA, ES, JS, DH, SB, SAM, AK, JC, NL, DF, UG, ABVM, GFS, FS, GJM and VS collected data and treated patients; KS and BH performed the cytogenetic analysis; SB, SAM, NL and AK contributed to the study experiments; DH, VS, GFS, FS and GJM commented on the paper; all the authors reviewed and approved the paper.

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Correspondence to Elena Crisà.

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EC, AGK, VA, ES, JS, DH, KS, SB, SAM, AK, JC, NL, DF, UG, BH, ABVM, FS and GJM have no conflict of interests; VS has received honoraria from honoraria da Celgene, Novartis, Takeda, Amgen, Astex and Janssen; GFS has received honoraria from and/or played an advisory role for AbbVie, Amgen, Böehringer-Ingelheim, Celgene, Helsinn Healthcare and Hoffmann—La Roche, Janssen—Cilag and Novartis. GFS and ES work at Hospital Universitario y Politécnico La Fe, which receives research funding and/or participates in multiple clinical trials funded by different pharmaceutical companies, including AbbVie, Amgen, Böehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Helsinn Healthcare and Hoffman—La Roche, Janssen—Cilag, Novartis and Onconova. GFS is also a member of the Spanish Group on Myelodysplastic Syndromes (Grupo Español de Síndromes Mielodisplásicos, GESMD), which is sponsored by Celgene and Novartis.

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Crisà, E., Kulasekararaj, A.G., Adema, V. et al. Impact of somatic mutations in myelodysplastic patients with isolated partial or total loss of chromosome 7. Leukemia 34, 2441–2450 (2020). https://doi.org/10.1038/s41375-020-0728-x

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