Multi-Center Study on Myelodysplastic Syndromes with Isolated Partial or Total Loss of Chromosome 7
Authors: Crisà Elena , Such Esperanza , Best Steven , Kulasekararaj Austin , Cervera José , Adema Vera , Lea Nicholas , Ferrero Dario , Allione Bernardino , Schanz Julie , Haase Detlef , Sanz Guillermo F. , Sole Francesco , Mufti Ghulam J. 
Published: October 2019

Abstract
Monosomy 7 is the second commonest abnormality in myelodysplastic syndrome (MDS). Recent studies (Cordoba et al 2012, Schanz et al 2012) have shown partial loss [del(7q)] of the chromosome (chr) is associated with better prognosis than total loss (-7). However it is still unclear if the biogenesis of these 2 abnormalities are separate or step wise progression of del(7q) to -7. Moreover monosomy 7 (-7) often occurs in the presence of other cytogenetic abnormalities which further adversely impacts the prognosis.
We designed a multicenter study to describe and compare clinical features, bone marrow characteristics, genetic profile and outcome of a large population of MDS patients with del(7q) or -7 as sole cytogenetic abnormality.
We retrospectively analysed 224 MDS patients who presented at diagnosis with the loss of chr. 7 as isolated cytogenetic abnormality or acquired it during follow up. We also performed a deep targeted mutational screen of the 24 commonest mutated genes in MDS.
Patients were included from the King’s College Hospital of London (n=75), the Spanish MDS group (n=107), the University of Medicine of Göttingen (n=35) and the "Città della Salute e della Scienza" hospital of Turin (n=11).
Fifty-five patients presented with isolated del(7q) and 169 with isolated -7. Median age at diagnosis was 69 and 64 years old in the two groups, respectively (p n.s.). According to WHO classification 18 patients had refractory anemia (RA), 3 RA with ring sideroblasts (RARS), 61 refractory cytopenia with multilineage dysplasia (RCMD), 42 RA with exces of blasts type 1 (RAEB-1), 53 RAEB-2, 25 MDS/MPN (MDS/Myeloproliferative neoplasm) and 8 MDS unclassified. Fourteen patients with bone marrow blasts percentage between 20 and 30% were also included.
MDS with excess of blasts type 1 or 2 were more frequent in the del(7q) group (56% vs. 42%) whereas MDS/MPN prevailed in the -7 group (14% vs. 4%), p=0.049. At diagnosis, del(7q) patients had a higher platelet count whereas there were no differences in neutrophils count and haemoglobin between the two groups; despite similar basal haemoglobin levels a higher number of patients with del(7q) was transfusion dependent (52% vs. 32%, p=0.015).
Regarding the mutational status, we have so far analysed 55 patients, 45 with del(7q) and 10 with -7. Overall we found 118 different allele variants (37 previously described as somatic mutations in cancer) across 24 myeloid genes commonly mutated in MDS. Sixty-four percent of patients had 1 or more previously described mutations, with a range of 1 to 6 mutations per patient (median 1). The genes involved in epigenetic modification were the most commonly mutated (in 36% of patients). Genes encoding for spliceosome components, signalling factors, transcriptional factors and STAG2 were mutated in 29%, 22%, 16% and 2% of patients respectively. There were no differences in mutation distribution between patients with -7 and patients with del(7q).
Median survival for the whole cohort was 23 months and was significantly affected by WHO diagnosis and, interestingly, by bone marrow cellularity: patients with hypocellular marrow at diagnosis had a better outcome with a median survival of 38 months, compared to 26 and 23 for normocellular and hypercellular marrow respectively (p= 0.031).
Patients with isolated del(7q) had a trend towards longer survival than patients with -7 (32 vs. 23 months), but this difference was not statistically significant.
Overall 30% of patients were treated with azacytidine, 20% with intensive chemotherapy, 5% with immunosuppressive drugs and 5% with other therapies, including lenalidomide; 46 patients (20.5%) underwent allogeneic transplantation and this significantly impacted on survival (median survival 35 months for transplanted patients vs. 22 for not-transplanted ones, p=0.002), regardless of induction treatment or cytogenetic status.
In conclusion, although patients with del(7q) had worse disease characteristics (excess of blasts and transfusion dependence), they showed a trend towards a better survival than those with -7. Preliminary data on the genetic profile showed a prevalence of mutations in the genes involved in epigenetic regulation with no significant differences between the partial and total loss of chr.7.

Disclosures
No relevant conflicts of interest to declare.