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Deletion of 5q is one of the most frequent cytogenetic aberrations in myelodysplastic syndromes (MDS). The WHO category of myelodysplastic syndrome with isolated del(5q) describes an own entity showing good prognosis and also demonstrating response to specific treatment such as lenalidomide. However, in some patients the disease evolves to secondary AML. The underlying pathogenic mechanisms are still under debate. Recently, CSNK1A1 was found to be frequently mutated in MDS with del(5q) irrespective of the presence of additional cytogenetic lesions. CSNK1A1 is located on 5q32 in the commonly deleted region.

To analyze mutations in CSNK1A1 in correlation to other gene mutations as well as to clinical data and prognostic information in MDS with isolated del(5q).

We investigated 115 patients (82 female, 33 male) presenting with MDS with isolated del(5q) that were strictly diagnosed according to WHO classification 2008 with respect to cytomorphology and cytogenetics (blasts below 5% in the bone marrow and 5q deletion sole). All patients were analyzed for mutations in ASXL1, BCOR, BRAF, CBL, CSNK1A1, DNMT3A, ETV6, EZH2, FLT3-TKD, GATA1, GATA2, IDH1, IDH2, JAK2, KIT, NRAS, KRAS, MPL, NPM1, PHF6, RUNX1, SF3B1, SRSF2, TET2, TP53, U2AF1, and WT1. The libraries were generated with the ThunderStorm (RainDance Technologies, Billerica, MA) and the Access Array System (Fluidigm, San Francisco, CA) and both libraries were sequenced on a MiSeq instrument (Illumina, San Diego, CA). Missense variants not yet described in any public database were excluded from statistical analyses.

In the total cohort the most frequently mutated genes were DNMT3A and TP53 (21/115, 18% each), followed by SF3B1 (18/115, 16%), TET2 (13/113, 12%), CSNK1A1 (11/115, 10%), ASXL1 (9/115, 8%), and JAK2 (7/115, 6%). The mutation frequencies of all other analyzed genes were below 5%, respectively. In only 35/115 patients (30%) no gene mutation was identified. Therefore, CSNK1A1 is the fifth most frequently mutated gene in MDS with isolated del(5q). All CSNK1A1 mutations were missense mutations in either amino acid Glu98 (n=9) or Asp140 (n=2). Investigating concomitant gene mutations with CSNK1A1 mutations resulted in two cases showing no additional gene mutation. The other nine cases showed mutations in ASXL1 (n=2), DNMT3A (n=2), SF3B1 (n=3), SRSF2, TET2, or U2AF1, respectively. Interestingly, five of the eleven cases (46%) presented with an additional mutation in one of the spliceosomal genes SF3B1 (n=3), SRSF2 (n=1), or U2AF1 (n=1) (vs only 16% in CSNK1A1 wildtype, p=0.034). No correlation of CSNK1A1 mutations with age, sex, white blood cell count, hemoglobin level, platelet count, as well as bone marrow blast count were found. There was also no prognostic impact of CSNK1A1 mutations on overall survival. Furthermore we raised the question if the CSNK1A1 mutations occur more likely in the del(5q) cell clone or in the remaining cells. Therefore, we compared the percentage of del(5q) positive cells by evaluation of the corresponding FISH data with the mutation load of CSNK1A1 and found a significant correlation (r=0.761, p=0.006), suggesting that CSNK1A1 mutations occur more likely in the del(5q) cell clone and is therefore affected on both alleles.

1) CSNK1A1 is the fifth most frequently mutated gene in MDS with isolated del(5q). 2) Cases with mutations in CSNK1A1 frequently associate with mutations in one of the spliceosomal genes SF3B1, SRSF2, or U2AF1. 3) CSNK1A1 mutations are most likely present in the del(5q) clone.