Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic myeloid neoplasms showing a predisposition to acute myeloid leukemia (AML). The recent discovery of novel pathway mutations of the RNA splicing machinery provided a new insight into the pathogenesis of MDS. These splicing pathway mutations are highly prevalent among all MDS subtypes, accounting for 45 to 85% of the cases. However, the frequency of mutations shows substantial variations among disease subtypes, the genetic/biological basis of which has not been clarified. In addition, the impact of splicing pathway mutations on prognosis has been poorly defined. To explore the genetic basis for these differences, we analyzed genome-wide copy number lesions and the spectrum of gene mutations that may coexist with splicing pathway mutations in a set of 283 cases with myelodysplasia, using SNP array karyotyping and target sequencing of common gene targets in MDS, including TET2 and EZH2. The effects of the splicing pathway mutations on clinical outcomes were evaluated together with those of these accompanying genetic lesions. Splicing pathway mutations were identified in 160 (57%) among 8 components of the splicing machinery, which occurred in a mutually exclusive manner. SNP array karyotyping revealed 138 cases (49%) showing copy number alterations, in which 7q- and/or 5q- were the most frequent abnormalities. Interestingly, the splicing pathway mutations were found at a significantly lower frequency among patients with 7q- and/or 5q- (p<0.0001), where multivariate analysis revealed that 7q- and/or 5q- were independently and significantly associated with the lower frequency of spliceosome mutation (p = 0.001 for 7q- and p = 0.029). 7q- and/or 5q- with complex karyotypes were associated with a significantly poor prognosis (p = 0.025, log-rank test), the presence of the splicing pathway mutations had no impact on prognosis. Interestingly, however, the presence of 7q- and/or 5q- do not seem to be a risk of poor prognosis among those patients carrying a splicing pathway mutation, suggesting that the presence of a splicing pathway mutation could have a beneficial effect on the prognosis of patients with 7q- and/or 5q-. In total, 172mutations were identified among 117 samples, including 41 TET2 (25%), 32 RUNX1 (20%), 26 ASXL1 (16%), 24 RAS (15%), 22 TP53 (14%), 17 IDH1/2 (10%), 10 CBL (6%) and 10 EZH2 (6%) mutations. No specific association between splicing pathway mutations and other coexisting mutations, except that the SRSF2 mutations were significantly associated with lower numbers of accompanying gene mutations compared with that of the U2AF35 mutations (N=14) (OR 6.2 95%CI 1.1-35), which may be of potential interest in the light of the previous report that SRSF2 was involved in the regulation of DNA stability and that depletion of SRSF2 can induce genomic stability.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5122. doi:1538-7445.AM2012-5122