title: Mutations in the Spliceosomal Machinery Genes SRSF2, U2AF1, and ZRSR2 and Response to Decitabine in Myelodysplastic Syndrome.
abstract: BACKGROUND
  Hypomethylating agents, such as azacitidine and decitabine, now constitute one of the mainstays of myelodysplastic syndrome (MDS) treatment. In recent years, novel recurrent mutations in multiple genes encoding RNA spliceosomal machinery (SRSF2, U2AF1, ZRSR2, SF3B1) were revealed. However, the clinical impact of these mutations on the outcomes of treatment of MDS patients with hypomethylating agents has not been described.
  
  
  METHODS
  A total of 58 de novo MDS patients were included in the study who had received first-line decitabine treatment. Polymerase chain reaction (PCR) followed by direct sequencing analyses was performed for the spliceosomal machinery genes including SRSF2, U2AF1 and ZRSR2.
  
  
  RESULTS
  In the present analysis of 58 Korean MDS patients, mutations in the splicing machinery genes SRSF2, U2AF1 and ZRSR2 were detected in 5 (8.6%), 10 (17.2%) and 6 (10.3%) patients, respectively, and the incidence of SRSF2 mutation was lower than those of previous series. The overall response rates (ORRs) including complete remission (CR), partial response (PR), and marrow CR (mCR) were 42.9% in the spliceosome wild-type (WT) group and 46.7% in the spliceosome-mutated group (p>0.999). The median OS was 22.0 months in the spliceosome-WT group and 15.9 months in the spliceosome-mutated group (p=0.267) CONCLUSION: This study firstly reports the impact of mutations of the spliceosomal machinery genes on the outcomes of decitabine treatment in MDS. The mutational status of the SRSF2, U2AF1 and ZRSR2 did not affect the response rate or survival in MDS patients who had received first-line decitabine treatment. Further studies are needed to confirm the prognostic relevance of spliceosome mutations to the clinical outcomes of treatment with hypomethylating agents.
authors.affiliation: Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jung Yong
authors.initials: JY
authors.lastname: Hong
authors.affiliation: Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Department of Laboratory Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea.
authors.forename: Ja-Young
authors.initials: JY
authors.lastname: Seo
authors.affiliation: Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Hyun Ae
authors.initials: HA
authors.lastname: Jung
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Silvia
authors.initials: S
authors.lastname: Park
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Kihyun
authors.initials: K
authors.lastname: Kim
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Chul Won
authors.initials: CW
authors.lastname: Jung
authors.affiliation: Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea.
authors.forename: Jin Seok
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Oncology-Hematology, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Joon Seong
authors.initials: JS
authors.lastname: Park
authors.affiliation: Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea hee_jin.kim@samsung.com jh21.jang@samsung.com.
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea hee_jin.kim@samsung.com jh21.jang@samsung.com.
authors.forename: Jun Ho
authors.initials: JH
authors.lastname: Jang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000077209:Decitabine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D012326:RNA Splicing / Q000235:genetics; D012261:Ribonucleoproteins / Q000235:genetics*; D000068103:Serine-Arginine Splicing Factors; D017381:Spliceosomes / Q000187:drug effects / Q000235:genetics; D000072668:Splicing Factor U2AF; D016896:Treatment Outcome
chemical_list: D009687:Nuclear Proteins; D012261:Ribonucleoproteins; D000072668:Splicing Factor U2AF; C076753:U2AF1 protein, human; C484334:ZRSR2 protein, human; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; D000077209:Decitabine; D001374:Azacitidine
keywords: Myelodysplastic syndrome; SRSF2; U2AF1; ZRSR2; decitabine