Poor Survival Outcomes In Myelodysplastic Syndrome Patients With Non-t(6;9) and Non-Inv(3) Balanced Chromosomal Rearrangements Are Influenced By SRSF2 Mutations
Authors: Ai Jing , Visconte Valeria , Tabarroki Ali , Hasrouni Edy , Hamilton Betty K. , Mukherjee Sudipto , Kalaycio Matt , Sobecks Ronald M. , Advani Anjali S. , Sekeres Mikkael A. , Shetty Shashirekha , Tiu Ramon V. 
Published: October 2019

Abstract
Cytogenetics is an important predictor of overall outcomes in patients with myeloid malignancies including myelodysplastic syndromes (MDS). Traditional metaphase cytogenetics can detect chromosomal abnormalities in 45-50% of MDS patients. Unbalanced chromosomal abnormalities including deletions, monosomies and others are the predominant lesions commonly encountered. The prognostic value of most of these unbalanced chromosomal changes is well established specifically -7/-7q, -5/-5q, and +8. However, the role played by balanced chromosomal rearrangements (BCR) specifically balanced translocations and inversions in MDS is less established. Most cases especially in the absence of poor prognostic chromosomal karyotypes are assigned by default to the intermediate risk group. The importance of BCR especially translocations cannot be underscored since novel fusion proteins may form during such chromosomal events that can be subsequently targeted similarly as in the prototypical disease bcr-abl positive chronic myeloid leukemia. We hypothesized that BCR are commonly found in MDS and may confer important prognostic and therapeutic impact. We studied a total of 303 MDS patients seen at the Cleveland Clinic between the years 2002-2011. There were 197 males and 106 females. The median age of the cohort is 69 years (range: 19-92). The median follow-up time is 17 months. Cytogenetic, hematologic and survival data were collected from individual patients. Responses were assessed using the International working group criteria for MDS. Categorical data were analyzed using X2 test and survival outcomes were analyzed using Kaplan-Meier method. A p-value of <0.05 was considered statistically significant. Sanger sequencing for genes relevant in MDS pathophysiology including TET2, CBL, DNMT3A, NRAS, KRAS, TP53, SF3B1, U2AF1, SRSF2, ASXL1, RUNX1, JAK2, IDH1/2 were performed according to previously published methods. Balanced rearrangements with known poor prognostic significance specifically t(6;9) and inv(3) were excluded from the analysis. A total of 23 patients with BCR (8%) were identified. The most commonly affected chromosomes are chromosomes 1 and 7 with primarily translocations including 2 cases each of t(7;8) and t(1;7); while inversions involved various chromosomes including 2, 4, 9, 10, and 11. To understand the prognostic significance of these BCR, we compared the survival outcomes of patients with BCR with those of patients with specific chromosomal defects prognostically defined using the IPSS. Patients with BCR have worse OS similar to patients with poor risk cytogenetics as defined by IPSS (BCR=7 mos vs [Good risk=23 mos, Int=15 mos, vs. poor=5 mos], p=.0013). We previously reported the prognostic importance of single nucleotide polymorphism array analysis (SNP-A) lesions in MDS. New SNP-A and acquired somatic uniparental disomy abnormalities did not alter the prognosis of patients with BCR (SNP-A: new lesions= 6.7 mos vs. no lesions= 6.7 mos; p=.57, UPD: new lesions=4.6 mos vs. no lesions=7.7 mos, p=.19). In the advent of molecular genetics, specific molecular mutations affect outcomes in MDS and related cancers. We investigated the frequency and the role played by specific molecular mutations in the outcomes of patients with BCR. Among detected somatic mutations (TET2 (9%), ASXL1 (17%), JAK2 (13%), TP53 (9%) and SRSF2 (9%)), only patient harboring mutations in the RNA splicing gene SRSF2 conferred worse outcomes in this group (MUT= 1 mo vs. WT= 9 mos, p=.001). Therapeutically, 3 patients underwent allogeneic hematopoietic cell transplant (Allo-HCT), 11 received pharmacologic therapies (Induction chemotherapy [IC]=3; hypomethylating therapy [HMT]=11) and 5 with supportive treatments. All patients who received Allo-HCT achieved a complete remission and remain alive while 2 patients who received IC and 7 patients who received HMT did not respond to treatment. In conclusion, BCR are not uncommon in MDS. Interestingly, even when excluding known poor-risk balanced translocations like t(6;9) and inv(3), they still conferred a poor survival outcome in MDS patients. RNA splicing gene mutations specifically SRSF2 is a driver of worse outcomes within this group. Patients with BCR have better outcomes when managed with allo-HCT compared to HMT and IC.

Disclosures:
No relevant conflicts of interest to declare.