NOTCH1 pathway activating mutations and clonal evolution in pediatric T-cell acute lymphoblastic leukemia.

Autor: Kimura S; Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.; Department of Pediatrics, Hiroshima University, Hiroshima, Japan., Seki M; Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan., Yoshida K; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Shiraishi Y; Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan., Akiyama M; Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan., Koh K; Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan., Imamura T; Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan., Manabe A; Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan., Hayashi Y; Gunma Children's Medical Center, Shibukawa, Japan., Kobayashi M; Department of Pediatrics, Hiroshima University, Hiroshima, Japan., Oka A; Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan., Miyano S; Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan., Ogawa S; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Takita J; Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.; Department of Pediatrics, Kyoto University, Kyoto, Japan.
Jazyk: angličtina
Zdroj: Cancer science [Cancer Sci] 2019 Feb; Vol. 110 (2), pp. 784-794. Date of Electronic Publication: 2019 Jan 09.
DOI: 10.1111/cas.13859
Abstrakt: Molecular mechanisms involved in the relapse of T-cell acute lymphoblastic leukemia (T-ALL) are not fully understood, although activating NOTCH1 signaling due to NOTCH1/FBXW7 alterations is a major oncogenic driver. To unravel the relevance of NOTCH1/FBXW7 mutations associated with relapse, we performed whole-exome sequencing in 30 pediatric T-ALL cases, among which 11 diagnosis-relapse paired cases were further investigated to track the clonal evolution of relapse using amplicon-based deep sequencing. NOTCH1/FBXW7 alterations were detected in 73.3% (diagnosis) and 72.7% (relapse) of cases. Single nucleotide variations in the heterodimerization domain were the most frequent (40.0%) at diagnosis, whereas proline, glutamic acid, serine, threonine-rich (PEST) domain alterations were the most frequent at relapse (54.5%). Comparison between non-relapsed and relapsed cases at diagnosis showed a predominance of PEST alterations in relapsed cases (P = .045), although we failed to validate this in the TARGET cohort. Based on the clonal analysis of diagnosis-relapse samples, we identified NOTCH1 "switching" characterized by different NOTCH1 mutations in a major clone between diagnosis and relapse samples in 2 out of 11 diagnosis-relapse paired cases analyzed. We found another NOTCH1 "switching" case in a previously reported Berlin-Frankfurt-Münster cohort (n = 13), indicating NOTCH1 importance in both the development and progression of T-ALL. Despite the limitations of having a small sample size and a non-minimal residual disease-based protocol, our results suggest that the presence of NOTCH1 mutations might contribute to the disease relapse of T-ALL.
(© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
Databáze: MEDLINE
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