Identification of cell-type-specific mutations in nodal T-cell lymphomas.
Recent genetic analysis has identified frequent mutations in ten-eleven translocation 2 (TET2), DNA methyltransferase 3A (DNMT3A), isocitrate dehydrogenase 2 (IDH2) and ras homolog family member A (RHOA) in nodal T-cell lymphomas, including angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified. We examined the distribution of mutations in these subtypes of mature T-/natural killer cell neoplasms to determine their clonal architecture. Targeted sequencing was performed for 71 genes in tumor-derived DNA of 87 cases. The mutations were then analyzed in a programmed death-1 (PD1)-positive population enriched with tumor cells and CD20-positive B cells purified by laser microdissection from 19 cases. TET2 and DNMT3A mutations were identified in both the PD1+ cells and the CD20+ cells in 15/16 and 4/7 cases, respectively. All the RHOA and IDH2 mutations were confined to the PD1+ cells, indicating that some, including RHOA and IDH2 mutations, being specific events in tumor cells. Notably, we found that all NOTCH1 mutations were detected only in the CD20+ cells. In conclusion, we identified both B- as well as T-cell-specific mutations, and mutations common to both T and B cells. These findings indicate the expansion of a clone after multistep and multilineal acquisition of gene mutations.
Department of Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.|Department of Hematology, Faculty of Medicine, University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam.|Stem Cell Transplantation Zone, Blood Transfusion Hematology Hospital, Ho Chi Minh City, Vietnam.
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Nguyen
Department of Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.|Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.|Department of Hematology, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan.
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Sakata-Yanagimoto
Department of Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
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Asabe
Department of Integrative Pathology, Jichii Medical University, Shimotsuke, Tochigi, Japan.
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D
Matsubara
Department of Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
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J
Kano
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Yoshida
Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
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Y
Shiraishi
Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
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K
Chiba
Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
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H
Tanaka
Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
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Miyano
Department of Hematology, Toranomon Hospital, Tokyo, Japan.|Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
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Izutsu
Department of Pathology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
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Nakamura
Pathology Project for Molecular Targets, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
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0000-0002-1599-5800
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Takeuchi
Department of Pathology, Kurume University, Kurume, Fukuoka, Japan.
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Miyoshi
Department of Pathology, Kurume University, Kurume, Fukuoka, Japan.
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Ohshima
Nanotechnology Innovation Station, National Institute for Materials Science, Tsukuba, Ibaraki, Japan.
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Minowa
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Ogawa
Department of Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
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Noguchi
Department of Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.|Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.|Department of Hematology, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan.
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Chiba
D000483:Alleles; D019943:Amino Acid Substitution; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor; D000090205:DNA Methyltransferase 3A; D015329:Gene Rearrangement, T-Lymphocyte; D020022:Genetic Predisposition to Disease; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007150:Immunohistochemistry; D016130:Immunophenotyping; D054391:Lymphoma, Extranodal NK-T-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009928:Organ Specificity / Q000235:genetics; D010641:Phenotype; D017422:Sequence Analysis, DNA; D060152:V(D)J Recombination; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D014408:Biomarkers, Tumor; C000717967:DNMT3A protein, human; D007143:Immunoglobulin Heavy Chains; D000090205:DNA Methyltransferase 3A; D020742:rhoA GTP-Binding Protein