title: Somatic mutations predict outcomes of hypomethylating therapy in patients with myelodysplastic syndrome.
abstract: Although hypomethylating therapy (HMT) is the first line therapy in higher-risk myelodysplastic syndromes (MDS), predicting response to HMT remains an unresolved issue. We aimed to identify mutations associated with response to HMT and survival in MDS. A total of 107 Korean patients with MDS who underwent HMT (57 responders and 50 non-responders) were enrolled. Targeted deep sequencing (median depth of coverage 1,623X) was performed for 26 candidate MDS genes. In multivariate analysis, no mutation was significantly associated with response to HMT, but a lower hemoglobin level (<10g/dL, OR 3.56, 95% CI 1.22-10.33) and low platelet count (<50,000/μL, OR 2.49, 95% CI 1.05-5.93) were independent markers of poor response to HMT. In the subgroup analysis by type of HMT agents, U2AF1 mutation was significantly associated with non-response to azacitidine, which was consistent in multivariate analysis (OR 14.96, 95% CI 1.67-134.18). Regarding overall survival, mutations in DNMT1 (P=0.031), DNMT3A (P=0.006), RAS (P=0.043), and TP53 (P=0.008), and two clinical variables (male-gender, P=0.002; IPSS-R H/VH, P=0.026) were independent predicting factors of poor prognosis. For AML-free survival, mutations in DNMT3A (P<0.001), RAS (P=0.001), and TP53 (P=0.047), and two clinical variables (male-gender, P=0.024; IPSS-R H/VH, P=0.005) were independent predicting factors of poor prognosis. By combining these mutations and clinical predictors, we developed a quantitative scoring model for response to azacitidine, overall- and AML-free survival. Response to azacitidine and survival rates became worse significantly with increasing risk-scores. This scoring model can make prognosis prediction more reliable and clinically applicable.
authors.affiliation: Integrated Research Center for Genome Polymorphism, Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Jung
authors.affiliation: Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Yoo-Jin
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Integrated Research Center for Genome Polymorphism, Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Seon-Hee
authors.initials: SH
authors.lastname: Yim
authors.affiliation: Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Hye-Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Yong-Rim
authors.initials: YR
authors.lastname: Kwon
authors.affiliation: Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Hur
authors.affiliation: Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Bon-Kwan
authors.initials: BK
authors.lastname: Goo
authors.affiliation: Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Yun-Suk
authors.initials: YS
authors.lastname: Choi
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Sug Hyung
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Integrated Research Center for Genome Polymorphism, Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Yeun-Jun
authors.initials: YJ
authors.lastname: Chung
authors.affiliation: Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Je-Hwan
authors.initials: JH
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D001374:Azacitidine / Q000627:therapeutic use*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects*; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000235:genetics; D049308:Dioxygenases; D005260:Female; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D000072668:Splicing Factor U2AF / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; D011518:Proto-Oncogene Proteins; D000072668:Splicing Factor U2AF; C076753:U2AF1 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D001374:Azacitidine
keywords: hypomethylating therapy; mutation; myelodysplastic syndrome; targeted sequencing