Eun-Hyung Yoo1, Kyung-Jin Park2,3, Hong-Hee Won2,3, Jun-Hee Park2,3, Jong-Ho Park2,3, Seung-Tae Lee4, Hee-Jin Kim4, Soo-Mee Bang5, Hyun-Sook Chi6, Chul Won Jung7, Sun-Hee Kim4, Hongseok Yun8, Choong-Hyun Sun8, Inho Park8, Seungmook Lee8, Clarence Lee9, Barry Merriman9, Raymond Luo10, Eileen Hwee Hong Tan10, Keun-Joon Park11, Na-Kyung Yoo11, Jason J Kang9, Jong-Won Kim12. 1. Department of Laboratory Medicine, Konyang University Hospital, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Korea. 2. Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea. 3. Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea. 4. Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. 5. Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea. 6. Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea. 7. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. 8. Samsung SDS, Seoul, Korea. 9. Thermo Fisher Scientific, Carlsbad, California. 10. Thermo Fisher Scientific, Singapore, Singapore. 11. Thermo Fisher Scientific, Seoul, Korea. 12. Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. kimjw@skku.edu.
Abstract
BACKGROUND: Despite recent advances in the investigation of myeloproliferative neoplasms (MPN), the impact of genetic heterogeneity on its molecular pathogenesis has not been fully elucidated. Thus, in this study, we aim to characterize the genetic complexity in Korean patients with polycythemia vera (PV) and essential thrombocythemia (ET). METHODS: We conducted association studies using 84 single-nucleotide polymorphisms (SNPs) in 229 patients (96 with PV and 133 with ET) and 170 controls. Further, whole-genome sequencing was performed in six patients (two with JAK2 V617F and four with wild-type JAK2), and putative somatic mutations were validated in a further 69 ET patients. Clinical and laboratory characteristics were also analyzed. RESULTS: Several germline SNPs and the 46 haplotype were significantly associated with PV and ET. Three somatic mutations in MPDZ, IQCH, and CALR genes were selected and validated. The frequency of the CALR mutation was 58.0% (40/69) in ET patients, who did not carry JAK2/MPL mutations. Moreover, compared with JAK2 V617F-positive patients, those with CALR mutations showed lower hemoglobin and hematocrit levels (P = 0.004 and P = 0.002, respectively), higher platelet counts (P =0.008), and a lower frequency of cytoreductive therapy (P = 0.014). CONCLUSION: This study was the first comprehensive investigation of the genetic characteristics of Korean patients with PV and ET. We found that somatic mutations and the 46 haplotype contribute to PV and ET pathogenesis in Korean patients.
BACKGROUND: Despite recent advances in the investigation of myeloproliferative neoplasms (MPN), the impact of genetic heterogeneity on its molecular pathogenesis has not been fully elucidated. Thus, in this study, we aim to characterize the genetic complexity in Korean patients with polycythemia vera (PV) and essential thrombocythemia (ET). METHODS: We conducted association studies using 84 single-nucleotide polymorphisms (SNPs) in 229 patients (96 with PV and 133 with ET) and 170 controls. Further, whole-genome sequencing was performed in six patients (two with JAK2 V617F and four with wild-type JAK2), and putative somatic mutations were validated in a further 69 ET patients. Clinical and laboratory characteristics were also analyzed. RESULTS: Several germline SNPs and the 46 haplotype were significantly associated with PV and ET. Three somatic mutations in MPDZ, IQCH, and CALR genes were selected and validated. The frequency of the CALR mutation was 58.0% (40/69) in ET patients, who did not carry JAK2/MPL mutations. Moreover, compared with JAK2 V617F-positive patients, those with CALR mutations showed lower hemoglobin and hematocrit levels (P = 0.004 and P = 0.002, respectively), higher platelet counts (P =0.008), and a lower frequency of cytoreductive therapy (P = 0.014). CONCLUSION: This study was the first comprehensive investigation of the genetic characteristics of Korean patients with PV and ET. We found that somatic mutations and the 46 haplotype contribute to PV and ET pathogenesis in Korean patients.
Authors: R Fu; M Xuan; Y Zhou; T Sun; J Bai; Z Cao; L Zhang; H Li; D Zhang; X Zhang; C Lv; F Xue; X Liu; R Yang; L Zhang Journal: Leukemia Date: 2014-04-15 Impact factor: 11.528
Authors: Stephen T Oh; Erin F Simonds; Carol Jones; Matthew B Hale; Yury Goltsev; Kenneth D Gibbs; Jason D Merker; James L Zehnder; Garry P Nolan; Jason Gotlib Journal: Blood Date: 2010-04-19 Impact factor: 22.113
Authors: Raajit Rampal; Fatima Al-Shahrour; Omar Abdel-Wahab; Jay P Patel; Jean-Philippe Brunel; Craig H Mermel; Adam J Bass; Jennifer Pretz; Jihae Ahn; Todd Hricik; Outi Kilpivaara; Martha Wadleigh; Lambert Busque; D Gary Gilliland; Todd R Golub; Benjamin L Ebert; Ross L Levine Journal: Blood Date: 2014-04-16 Impact factor: 22.113
Authors: Yana Pikman; Benjamin H Lee; Thomas Mercher; Elizabeth McDowell; Benjamin L Ebert; Maricel Gozo; Adam Cuker; Gerlinde Wernig; Sandra Moore; Ilene Galinsky; Daniel J DeAngelo; Jennifer J Clark; Stephanie J Lee; Todd R Golub; Martha Wadleigh; D Gary Gilliland; Ross L Levine Journal: PLoS Med Date: 2006-07 Impact factor: 11.069
Authors: Simon A Forbes; David Beare; Prasad Gunasekaran; Kenric Leung; Nidhi Bindal; Harry Boutselakis; Minjie Ding; Sally Bamford; Charlotte Cole; Sari Ward; Chai Yin Kok; Mingming Jia; Tisham De; Jon W Teague; Michael R Stratton; Ultan McDermott; Peter J Campbell Journal: Nucleic Acids Res Date: 2014-10-29 Impact factor: 16.971
Authors: Elisa Rumi; Daniela Pietra; Virginia Ferretti; Thorsten Klampfl; Ashot S Harutyunyan; Jelena D Milosevic; Nicole C C Them; Tiina Berg; Chiara Elena; Ilaria C Casetti; Chiara Milanesi; Emanuela Sant'antonio; Marta Bellini; Elena Fugazza; Maria C Renna; Emanuela Boveri; Cesare Astori; Cristiana Pascutto; Robert Kralovics; Mario Cazzola Journal: Blood Date: 2013-12-23 Impact factor: 22.113