MDS with Deletions in the Long Arm of Chromosome 11 Are Associated with a High Frequency of SF3B1 Mutations
Authors: Stengel Anna , Kern Wolfgang , Meggendorfer Manja , Haferlach Torsten , Haferlach Claudia 
Published: October 2019

Background: According to the revised International Prognostic Scoring System (IPSS-R), patients with MDS and deletions in the long arm of chromosome 11 (del(11q)) as sole abnormality are categorized as very good prognosis, even better than patients with a normal karyotype. Molecular data on this rare MDS subset is still limited.
Aims: Comprehensive cytogenetic and molecular genetic characterization of MDS patients with del(11q) with and without additional aberrations and evaluation of prognosis.
Patient cohorts and methods: Within 9225 unselected cases with de novo MDS, 33 cases with isolated del(11q) (del(11q) sole) and 23 cases with del(11q) accompanied by additional chromosomal aberrations (del(11q) other) were detected. All 56 cases were investigated using chromosome banding analysis (CBA) and interphase FISH. For 46 patients (33 of del(11)q sole, 13 of del(11q) other) material was available for investigation by genomic arrays (SurePrint G3 ISCA CGH+SNP Microarray, Agilent, Waldbronn, Germany). In 44 cases amplicon sequencing was performed to detect mutations in ASXL1, CALR, CBL, CSF3R, CSNK1A1, DNMT3A, ETNK1, ETV6, EZH2, FLT3-TKD GATA1, GATA2, IDH1, IDH2, JAK, KIT, KRAS, MPL, NPM1, NRAS, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1 and ZRSR2. Variants of unknown significance were excluded from statistical analysis. The cohort comprised 23 male and 33 female patients, median age was 75 years (range: 47-89 years).
Results: 33/9925 cases with del(11q) sole were found by CBA (0.4%). In the 23 del(11q) other cases additional aberrations included del(5q) (12/23 cases, 52%), del(20q) (3/23 cases, 13%), del(12p) (2/23 cases, 9%) and +8 (2/23 cases, 9%) as recurrent abnormalities. In 6/23 cases (26%), a complex karyotype (>3 aberrations) was observed.
In 13/33 cases with del(11q) sole by CBA, array CGH identified additional chromosomal aberrations (all non-recurrent, submicroscopic). In the total cohort analyzed by array CGH, the size of del(11q) varied between 12 - 58 Mb with a median of 39 Mb. In more detail, in cases with del(11q) sole the size ranged from 12 - 58 Mb (median: 38 Mb), in cases with del(11q) other from 21 - 56 Mb (median: 40 Mb). While the minimal deleted region for cases with del(11q) other was identified between genomic position 107 251 381 - 120 088 150, for cases with del(11q) sole no common minimal deleted region was determined due to the strong variation between the respective deleted regions.
Mutation analyses revealed a high frequency of SF3B1 mutations in the total cohort (47%). Mutation frequencies >10% were also detected for ASXL1 (17%), SRSF2 (13%), TET2 (13%) and U2AF1 (10%). The median number of mutations was 1 (range 0-4) without differences between both subgroups. However, the high frequency of SF3B1 mutations was even more prominent when only cases with del(11q) sole were analyzed (56% vs. 23% in del(11q) other). Moreover, mutations in U2AF1 were exclusively found in cases with del(11q) sole (14% vs. 0%). By contrast, mutations in ASXL1 were more frequent in del(11q) other (23% vs. 14%). However, these correlations were not found to be statistically significant due to the low number of cases. Comparison of the SF3B1 mutation loads with the proportion of cells with del(11q) observed by FISH revealed that in most cases, del(11q) is found in the main clone. Ring sideroblasts (≥15%) were detected in 11/45 cases (24%), 10 of them harbored an SF3B1 mutation. The minimal deleted region of del(11q) for SF3B1 mutated cases was identified between 107 789 141 - 119 437 544. In the total cohort, the overall survival (OS) at 5 years was 91% and is thus in line with the very good prognosis as defined by the IPSS-R. A lower OS at 5 years was observed for patients with del(11q) other compared to del(11q) sole, although it was not found to be statistically significant (94% vs. 85%).
Conclusion: In 0.4% of MDS patients a del(11q) sole was observed. This incidence is in line with data used for calculation of the IPSS-R (0.7% in Schanz et al., 2012). Especially in cases with del(11q) sole, but also in del(11q) other, a high frequency of SF3B1 mutations was observed, which might explain in part the very good prognosis as stated in the IPSS-R and also observed in the present study. Moreover, these patients were found to show a low number of other molecular mutations. The role of U2AF1 mutations, which were exclusively detected in cases with del(11q) sole, needs further investigation.

Disclosures
Stengel: MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.