Open AccessNOTCH 1 pathway activating mutations and clonal evolution in pediatric T‐cell acute lymphoblastic leukemia
Author(s) -
Kimura Shunsuke,
Seki Masafumi,
Yoshida Kenichi,
Shiraishi Yuichi,
Akiyama Masaharu,
Koh Katsuyoshi,
Imamura Toshihiko,
Manabe Atsushi,
Hayashi Yasuhide,
Kobayashi Masao,
Oka Akira,
Miyano Satoru,
Ogawa Seishi,
Takita Junko
Publication year - 2019
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13859
Subject(s) - notch signaling pathway , exome sequencing , somatic evolution in cancer , biology , mutation , minimal residual disease , notch 1 , cancer research , clone (java method) , leukemia , oncology , cancer , medicine , immunology , genetics , gene
Molecular mechanisms involved in the relapse of T‐cell acute lymphoblastic leukemia (T‐ ALL ) are not fully understood, although activating NOTCH 1 signaling due to NOTCH 1/ FBXW 7 alterations is a major oncogenic driver. To unravel the relevance of NOTCH 1/ FBXW 7 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. NOTCH 1/ FBXW 7 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 NOTCH 1 “switching” characterized by different NOTCH 1 mutations in a major clone between diagnosis and relapse samples in 2 out of 11 diagnosis‐relapse paired cases analyzed. We found another NOTCH 1 “switching” case in a previously reported Berlin‐Frankfurt‐Münster cohort (n = 13), indicating NOTCH 1 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 NOTCH 1 mutations might contribute to the disease relapse of T‐ ALL .