Molecular Mutations in U2AF1 Are Most Commonly Found in Del20q Myelodysplastic Syndromes but Do Not Lead to Poor Prognosis in This Karyotypic Subtype
Authors: Tabarroki Ali , Zhang Li , Visconte Valeria , Bupathi Manoj , Rogers Heesun J. , Makishima Hideki , Traina Fabiola , Hamilton Betty K. , Hasrouni Edy , Clemente Michael J. , de Melo Campos Paula , Duong Hien K. , Advani Anjali , Sekeres Mikkael A. , Copelan Edward A. , Tiu Ramon V. 
Published: October 2019

Abstract
Abstract 3804
Del20q is a commonly detected chromosomal abnormality in myelodysplastic syndromes (MDS) and myelofibrosis (MF). In MDS, del20q is a favorable cytogenetic lesion while in MF it is considered an intermediate risk karyotype. We hypothesized that the heterogeneity observed in del20q patients (pts) stems from the acquisition of various mutations during the pts' disease course. These additional chromosomal and/or new molecular defects may help explain these differences. We studied a total of 127 pts with del20q identified either by MC or single polymorphism array (SNP-A). Most pts are male (N=86) and the median age of the cohort is 70 years. The median follow-up time is 24 months. Most pts have MDS (N=76) while the rest are MDS/MPN (N=10), MPN (N=16), sAML (N=18), and other hematological malignancies (N=7). Hematologic parameters, bone marrow (BM) results and clinical data including IPSS, cytogenetics, transfusion requirements, treatment response, overall survival (OS) and progression free survival (PFS) as defined by IWG criteria were collected. We utilized chi-square and Fischer-exact test to compare descriptive variables. Kaplan-Meier statistics were used to compare survival differences between groups and Cox proportional hazard ratio to determine factors that are predictive of outcomes in these pts. A p-value of ≤0.05 is considered statistically significant. Phenotypically, pts with isolated del20q (iso-del20q) have higher ANC, WBC, less splenomegaly and BM blasts. Survival differences were noted between pts with del20q± additional chromosomal defects with better OS noted in pts with iso-del20q compared to del20q with 1 additional cytogenetic abnormality (del20q+1), and del20q with 2 or more cytogenetic abnormalities (del20q+≥2) (OS: 93 vs 52 vs 64 mos, p=.04; PFS: 24 vs 17 vs 6 mos, p=.005; and EFS: 42 vs 38 vs 12 mos, p=.002). Furthermore, PFS is better in iso-del20q compared to del20q+1 and del20q+≥2 pts (24 vs 17 vs 8 mos, p =.005). After defining key differences in survival in pts with del20q, we sought to investigate the biological rationale for these differences. Whole exome sequencing was performed in 4 pts with del20q. Initial candidate genes, SULF2 and PMEPA1 were WT. Analysis showed involvement of U2AF1 which was further confirmed as somatic. Direct sequencing of U2AF1 in this cohort revealed mutations in 25% of pts. Interestingly, among chromosomal subtypes, U2AF1 mutations are most frequently found in pts with del20q (25% (del 20q) vs 3% (−7/-7q) vs 1.6% (normal) vs 0.5% (+8 and −5q). Moreover, in our cohort, U2AF1 is the most frequently mutated gene in the iso-del20q suggesting a strong correlation between this gene and the pathogenesis of del20q. However, U2AF1 has been associated with poor outcomes. In fact, in our MDS cohort (N=340) (Hasrouni E et al. Abstract # 53469), the median OS of U2AF1 mutants (MUT) vs WT are 7 mos vs 20 mos, p =.010 for the whole cohort and remained poor even in normal karyotype MDS (median OS=4 vs 28 mos; p =.0004). Pts with del20q and U2AF1 mutations have excellent survival (median OS=85 mos) suggesting an alternative mechanism whereby U2AF1 modulates this MDS subtype or the presence of another pathway that suppresses the negative effects of U2AF1 mutations in this karyotypic subtype. These findings are reminiscent of the good outcomes correlated with SF3B1 mutations, which we recently found to be associated with lower levels of DNA damage (Visconte V. et al. Abstract # 55089). Interestingly, U2AF1 MUT del20q have lower gamma-H2AX levels compared to U2AF1 MUT in other choromosmal subtypes (5.17±4.68 vs 34.53±30.51) and this may explain decreased propensity for AML transformation in this group. Also, we performed direct sequencing for genes associated with poor (CBL, IDH1/2, DNMT3A, ASXL1, NRAS/KRAS, TP53, EZH2) and good (SF3B1) prognostic outcomes in MDS and found a lower frequency of poor prognostic molecular defects in iso-del20q compared to del20q + ≥2 (22% vs 81%; p=.004). Elucidation of downstream targets by RNA sequencing in del20q cases particularly those with U2AF1 mutations are underway. In addition, screening for mutations involving genes reported to be important in del20q malignancies, like PTPN1 and L3MBTL1 was negative. In summary, pts with del20q have a characteristic clinical profile associated with low risk disease. Iso-del20q have better OS compared to pts with del20q+1 and del20q+≥2 even in the presence of U2AF1 mutations.

Disclosures:
No relevant conflicts of interest to declare.