Genome-wide DNA methylation is predictive of outcome in juvenile myelomonocytic leukemia

Elliot Stieglitz; Tali Mazor; Adam B Olshen; Huimin Geng; Laura C Gelston; Jon Akutagawa; Daniel B Lipka; Christoph Plass; Christian Flotho; Farid F Chehab; Benjamin S Braun; Joseph F Costello; Mignon L Loh

doi:10.1038/s41467-017-02178-9

Genome-wide DNA methylation is predictive of outcome in juvenile myelomonocytic leukemia

Nat Commun. 2017 Dec 19;8(1):2127. doi: 10.1038/s41467-017-02178-9.

Authors

Elliot Stieglitz^{1

2}, Tali Mazor³, Adam B Olshen^{4

5}, Huimin Geng⁶, Laura C Gelston⁷, Jon Akutagawa⁷, Daniel B Lipka^{8

9

10}, Christoph Plass^{8

11}, Christian Flotho^{11

12}, Farid F Chehab¹³, Benjamin S Braun^{7

4}, Joseph F Costello³, Mignon L Loh^{14

15}

Affiliations

¹ Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, 1450 3rd Street, San Francisco, CA, 94158, USA. elliot.stieglitz@ucsf.edu.
² Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 3rd Street, San Francisco, CA, 94158, USA. elliot.stieglitz@ucsf.edu.
³ Department of Neurological Surgery, University of California, San Francisco, 1450 3rd Street, Room 471, San Francisco, CA, 94158, USA.
⁴ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 3rd Street, San Francisco, CA, 94158, USA.
⁵ Department of Epidemiology and Biostatistics, University of California, San Francisco, 550 16th Street, Box 0560, San Francisco, CA, 94158, USA.
⁶ Departments of Laboratory Medicine and Cellular and Molecular Pharmacology, University of California, 513 Parnassus Avenue, 1457A, Box 0451, San Francisco, CA, 94143, USA.
⁷ Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, 1450 3rd Street, San Francisco, CA, 94158, USA.
⁸ Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
⁹ Department of Hematology and Oncology, Medical Center, Otto-von-Guericke-University, Leipziger Str. 44, 39120, Magdeburg, Germany.
¹⁰ Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University, Leipziger Str. 44, 39120, Magdeburg, Germany.
¹¹ German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
¹² Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.
¹³ Department of Laboratory Medicine, University of California, San Francisco, 185 Berry Street Bldg B 290, Box 0134, San Francisco, CA, 94158, USA.
¹⁴ Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, 1450 3rd Street, San Francisco, CA, 94158, USA. mignon.loh@ucsf.edu.
¹⁵ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 3rd Street, San Francisco, CA, 94158, USA. mignon.loh@ucsf.edu.

Abstract

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder of childhood caused by mutations in the Ras pathway. Outcomes in JMML vary markedly from spontaneous resolution to rapid relapse after hematopoietic stem cell transplantation. Here, we hypothesized that DNA methylation patterns would help predict disease outcome and therefore performed genome-wide DNA methylation profiling in a cohort of 39 patients. Unsupervised hierarchical clustering identifies three clusters of patients. Importantly, these clusters differ significantly in terms of 4-year event-free survival, with the lowest methylation cluster having the highest rates of survival. These findings were validated in an independent cohort of 40 patients. Notably, all but one of 14 patients experiencing spontaneous resolution cluster together and closer to 22 healthy controls than to other JMML cases. Thus, we show that DNA methylation patterns in JMML are predictive of outcome and can identify the patients most likely to experience spontaneous resolution.

Publication types

Clinical Trial
Observational Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / therapeutic use
Biopsy
Child
Child, Preschool
DNA Methylation*
Disease-Free Survival
Female
Genome, Human / genetics*
Hematopoietic Stem Cell Transplantation
Humans
Infant
Kaplan-Meier Estimate
Leukemia, Myelomonocytic, Juvenile / blood
Leukemia, Myelomonocytic, Juvenile / genetics*
Leukemia, Myelomonocytic, Juvenile / mortality
Leukemia, Myelomonocytic, Juvenile / therapy
Male
Monocytes
Mutation
Neoplasm Regression, Spontaneous / genetics*
Prognosis
Prospective Studies

Substances

Antineoplastic Agents

Abstract

Publication types

MeSH terms

Substances

Grants and funding