Myelodysplastic Syndromes (MDS) With 20q Deletion Show a High Frequency Of Associated Cytogenetic and Molecular Lesions With An Association To U2AF1, SRSF2, and Prognostically Adverse ASXL1 Mutations

In patients with myelodysplastic syndromes (MDS), a 20q deletion [del(20q)] is considered to define a cytogenetic subgroup and, if present as a sole cytogenetic aberration, is associated with a favorable prognosis according to the revised IPSS (IPSS-R). However, associated genetic lesions and their prognostic impact in MDS with del(20q) remain to be clarified.

We studied 305 MDS patients with del(20q) for associated molecular and cytogenetic markers and clinical outcomes. All patients (229 males/76 females; median age, 74 yrs) were investigated by cytomorphology (CM) and chromosome banding analysis (CBA). Additionally, subsets were characterized by fluorescence in situ hybridization (FISH), molecular genetics including high-throughput sequencing (NGS), and array comparative genomic hybridization (aCGH).

A total of 210 (68.9%) patients had “early” MDS with blasts below 5%, and 95 (31.1%) “advanced” MDS i.e. RAEB-1/-2. When only patients with a sole del(20q) (n=217) were considered, 161 (74.2%) had early MDS, 56 (25.8%) had advanced MDS. This confirmed the preponderance of good-risk MDS subtypes in patients with del(20q). Additional chromosomal aberrations (ACAs), e.g. -Y, del(5q), -7/del(7q), and +8, were detected in 88/305 (28.9%) patients. Cytogenetic complexity was higher in advanced MDS patients as they showed a higher frequency of ACAs than early MDS (39/95; 41.1% vs. 49/210; 23.3%; P=0.003) and a higher mean number of ACAs (mean±SD, 1.3±2.7 vs. 0.6±1.5; P=0.020). The minimal commonly deleted region (CDR) was determined using aCGH (n=30 investigated) and was located from position 41,067,253 to 45,700,000 on 20q13.11-q13.12 (4.6 Mb in size). The flanking genes of the minimal CDR were PTPRT (receptor-type tyrosine-protein phosphatase T) on 20q13.11 and EYA2 (Eyes Absent Homolog 2) on 20q13.12. A total of 159 patients (104 early MDS, 55 advanced MDS) were investigated for additional molecular mutations, 82 patients (51.6%) had at least one mutation. The mean number of molecular mutations per patient was higher in advanced MDS as compared to early MDS (0.9±0.9 vs. 0.6±0.7; P=0.060). In detail, spliceosome mutations were frequent (U2AF1: n=28/140 investigated; 20.0%; SRSF2: n=29/159; 18.2%; SF3B1: n=8/159; 5.0%) and were mutually exclusive and equally distributed in early und advanced MDS. ASXL1mut which were found in 25/153 cases (16.3%) investigated in the total cohort showed a significantly lower frequency in early MDS as compared to advanced MDS (9/100; 9.0%; vs. 16/53; 30.2%; P=0.001). Lower mutation frequencies we observed for RUNX1 (14/157; 8.9%) and MLL-PTD (2/134; 1.5%). The 2-year overall survival (2-yr OS) was better in patients with early MDS as compared to advanced MDS (92.3% vs. 73.7%; P=n.s.). Patients with a sole del(20q) showed similar 2-yr OS to patients with del(20q) and occurrence of ACAs (87.1% vs 81.1%, P=n.s.). Patients with ASXL1mut had significantly worse 2-yr OS as compared to wild-type ASXL1 (45.5% vs 87.9%; P=0.002). The SRSF2 and U2AF1 mutation status did not significantly impact survival.

The cytogenetic subgroup of MDS with del(20q) has a good prognosis but may be further subclassified by additional cytogenetic and molecular lesions. U2AF1 mutations were overrepresented in MDS with del(20q) as compared to published frequencies in overall MDS. ASXL1 mutations were relevant for disease progression. Therefore, analyses of molecular mutations may contribute to prognostication and to therapeutic decisions in patients with MDS and del(20q).

Bacher:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Zenger:MLL Munich Leukemia Laboratory: Employment. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Roller:MLL Munich Leukemia Laboratory: Employment. Grossmann:MLL Munich Leukemia Laboratory: Employment. Krauth:MLL Munich Leukemia Laboratory: Employment. Jeromin:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.