1. Simple and robust methylation test for risk stratification of patients with juvenile myelomonocytic leukemia
- Author
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Hideki Muramatsu, Yusuke Okuno, Motoharu Hamada, Seiji Kojima, Atsushi Narita, Norihiro Murakami, Mignon L. Loh, Kotaro Narita, Daisuke Ichikawa, Elliot Stieglitz, Manabu Wakamatsu, Hironobu Kitazawa, Asahito Hama, Nozomu Kawashima, Rieko Taniguchi, Kyogo Suzuki, Shinsuke Kataoka, Yoshiyuki Takahashi, Nobuhiro Nishio, Eri Nishikawa, and Kosuke Aoki
- Subjects
Oncology ,medicine.medical_specialty ,Pediatric Cancer ,Concordance ,Restriction enzyme analysis ,Juvenile ,Context (language use) ,Risk Assessment ,Rare Diseases ,methylation test that ,Internal medicine ,Genetics ,medicine ,Humans ,Child ,Preschool ,Myeloproliferative neoplasm ,JMML ,Cancer ,Pediatric ,Leukemia ,Myeloid Neoplasia ,Juvenile myelomonocytic leukemia ,international consen ,business.industry ,Prevention ,robust DNA ,Hematopoietic Stem Cell Transplantation ,Infant ,Myelomonocytic ,Hematology ,Methylation ,DNA Methylation ,medicine.disease ,sus de fi nition for ,Leukemia, Myelomonocytic, Juvenile ,Child, Preschool ,DNA methylation ,Risk stratification ,business - Abstract
Key Points A total of 137 patients with JMML were analyzed using DREAM.We developed a robust DNA methylation test that is highly consistent with the array-based international consensus definition for JMML., Visual Abstract, Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative neoplasm that develops during infancy and early childhood. The array-based international consensus definition of DNA methylation has recently classified patients with JMML into the following 3 groups: high (HM), intermediate (IM), and low methylation (LM). To develop a simple and robust methylation clinical test, 137 patients with JMML were analyzed using the Digital Restriction Enzyme Analysis of Methylation (DREAM), which is a next-generation sequencing–based methylation analysis. Unsupervised consensus clustering of the discovery cohort (n = 99) using DREAM data identified HM (HM_DREAM; n = 35) and LM subgroups (LM_DREAM; n = 64). Of the 98 cases that could be compared with the international consensus classification, 90 HM (n = 30) and LM (n = 60) cases had 100% concordance with DREAM clustering results. Of the remaining 8 cases comprising the IM group, 4 were classified as belonging to the HM_DREAM group and 4 to the LM_DREAM group. A machine-learning classifier was successfully constructed using a support vector machine (SVM), which divided the validation cohort (n = 38) into HM (HM_SVM, n = 18) and LM (LM_SVM; n = 20) groups. Patients with the HM_SVM profile had a significantly poorer 5-year overall survival rate than those with the LM_SVM profile. In conclusion, we developed a robust methylation test using DREAM for patients with JMML. This simple and straightforward test can be easily incorporated into diagnosis to generate a methylation classification for patients so they can receive risk-adapted treatment in the context of future clinical trials.
- Published
- 2021