Details

Autor(en) / Beteiligte

• Kaburagi, Taeko
• Yamato, Genki
• Shiba, Norio
• Yoshida, Kenichi
• Hara, Yusuke
• Shiraishi, Yuichi
• Ohki, Kentaro
• Sotomatsu, Manabu
• Arakawa, Hirokazu
• Matsuo, Hidemasa
• Shimada, Akira
• Taki, Tomohiko
• Kiyokawa, Nobutaka
• Tomizawa, Daisuke
• Horibe, Keizo
• Miyano, Satoru
• Taga, Takashi
• Adachi, Souichi
• Ogawa, Seishi
• Hayashi, Yasuhide

Titel

Recurrent Gene Mutations in Pediatric Patients with AML By Targeted Sequencing ―the Jccg Study, JPLSG AML-05

Ist Teil von

• Blood, 2019-11, Vol.134 (Supplement_1), p.2697-2697

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2019

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Introduction Treatment outcomes of pediatric acute myeloid leukemia (AML) have improved via stratification therapy. However, relapse and mortality are still observed in 40% and 30% patients, respectively. Recently, comprehensive analyses using next-generation sequencing have revealed novel genetic alterations in adult AML patients, but insufficient analyses have been performed in pediatric AML patients. Further studies are warranted to evaluate the relationship between a more detailed genetic background and prognosis in pediatric AML patients. Methods We performed targeted sequencing using a 343-gene custom panel and next-generation sequencer in 302 pediatric patients with de novo AML who participated in the Japanese AML-05 study conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group from 2006 to 2010. One hundred and twenty patients with core binding factor (CBF)-AML, 52 with KMT2A rearrangements, 56 with normal karyotype (NK), 18 with complex karyotype (CK), and 57 with other karyotypes except for patients with acute megakaryocytic leukemia were enrolled. Correlations among gene mutations, other cytogenetic alterations, and clinical characteristics were investigated. Results and Discussion We found the following 6 recurrent gene mutations, which have not been frequently reported in pediatric AML: KMT2C (n = 13, 4.3%), PHF6 (n = 6, 2.0%), MGA (n = 13, 4.3%), TET2 (n = 11, 3.6%), JAK3 (n = 12, 4.0%), and GATA2 (n = 11, 3.6%). KMT2C mutations have been reported in adult and pediatric patients with CBF-AML and in a few patients with other types of AML; however, their clinical significance has not been revealed. Six of 13 patients with KMT2C mutations were found in CBF-AML, whereas the other 7 patients were detected in non CBF-AML (1 patient in KMT2A-rearrangement, 1 in CK, and 5 in other karyotypes). Loss of function mutations in KMT2C have also been reported to be associated with chemotherapy resistance in pediatric AML patients. Although no significant differences were found, 4 of 13 patients with KMT2C mutations did not achieve complete remission (p = .072), and 3 patients relapsed in <12 months. Significant differences were observed in event-free survival (EFS) between patients with and without KMT2C mutations (3-year EFS 36.9% vs. 56.8%; p = .019). In adult AML, PHF6 mutations have been detected in 3% of patients and have been reported as poor prognostic factors. In 6 patients with PHF6 mutations, 3 patients had a normal karyotype, and 2 patients had a complex karyotype. No PHF6 mutations were detected in AML patients with CBF or KMT2A rearrangements. PHF6 mutations were significantly frequently detected in AML patients with myelodysplasia-related changes (4/6, p = .008). Although 5 of 6 patients with PHF6 mutations archived complete remission, finally, 5 patients relapsed or died. There were significant differences in EFS between patients with or without PHF6 mutations (3-year EFS 16.7% vs. 58.2%; p = .041). MGA mutations have been reported thus far in a few AML patients. MGA is a negative regulator of MYC signaling; thus, loss of functions of MGA is considered to contribute to tumorigenesis. However, the clinical significance of MGA mutations has not been reported. MGA mutations were significantly frequently detected in AML patients with FAB M2 (7/13, p = .020). In our cohort, 2 of 3 AML patients with DEK-NUP214 had MGA mutations (p = .004). We did not find correlations between MGA mutations and prognosis (3-year OS 83.3% vs. 75.5%; p= .488, 3-year EFS 66.7% vs. 56.7%; p = .507) TET2 mutations have been found in 8%-19% of adult AML cases and are considered poor prognostic factors. In previous reports, TET2 mutations were also detected in 3.8% of pediatric AML patients, but because of the small number of patients, the association between TET2 mutations and prognosis has not been revealed. TET2 mutations were significantly frequently detected in older AML patients (median age 13.95 vs. 9.0 years; p = .022) and in AML patients with NK (5/11, p = .035). Contrary to previous reports on adult AML, TET2 mutations were not associated with prognosis (3-year OS 77.9% vs. 75.9%; p= .688, 3-year EFS 54.5% vs. 57.4%; p = .907). This suggested that TET2 mutations have a different clinical significance between adult and pediatric AML patients. In conclusion, mutations in the KMT2C and PHF6 genes were associated with poor prognosis, but TET2 mutations were not. Further analysis should be needed about TET2 mutations. Ogawa:ChordiaTherapeutics, Inc.: Consultancy, Equity Ownership; Kan Research Laboratory, Inc.: Consultancy; RegCell Corporation: Equity Ownership; Asahi Genomics: Equity Ownership; Qiagen Corporation: Patents & Royalties; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding.