title: JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma.
abstract: Epitheliotropic intestinal T-cell lymphoma (EITL, also known as type II enteropathy-associated T-cell lymphoma) is an aggressive intestinal disease with poor prognosis and its molecular alterations have not been comprehensively characterized. We aimed to identify actionable easy-to-screen alterations that would allow better diagnostics and/or treatment of this deadly disease. By performing whole-exome sequencing of four EITL tumor-normal pairs, followed by amplicon deep sequencing of 42 tumor samples, frequent alterations of the JAK-STAT and G-protein-coupled receptor (GPCR) signaling pathways were discovered in a large portion of samples. Specifically, STAT5B was mutated in a remarkable 63% of cases, JAK3 in 35% and GNAI2 in 24%, with the majority occurring at known activating hotspots in key functional domains. Moreover, STAT5B locus carried copy-neutral loss of heterozygosity resulting in the duplication of the mutant copy, suggesting the importance of mutant STAT5B dosage for the development of EITL. Dysregulation of the JAK-STAT and GPCR pathways was also supported by gene expression profiling and further verified in patient tumor samples. In vitro overexpression of GNAI2 mutants led to the upregulation of pERK1/2, a member of MEK-ERK pathway. Notably, inhibitors of both JAK-STAT and MEK-ERK pathways effectively reduced viability of patient-derived primary EITL cells, indicating potential therapeutic strategies for this neoplasm with no effective treatment currently available.
authors: Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors: M-L
authors: ML
authors: Nairismägi
authors: Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.|Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.|Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
authors: J
authors: J
authors: Tan
authors: Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors: J Q
authors: JQ
authors: Lim
authors: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.|Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
authors: S
authors: S
authors: Nagarajan
authors: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.|Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
authors: C C Y
authors: CC
authors: Ng
authors: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.|Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
authors: V
authors: V
authors: Rajasegaran
authors: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.|Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
authors: D
authors: D
authors: Huang
authors: Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors: W K
authors: WK
authors: Lim
authors: Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors: Y
authors: Y
authors: Laurensia
authors: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.|Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
authors: G C
authors: GC
authors: Wijaya
authors: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.|Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
authors: Z M
authors: ZM
authors: Li
authors: Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.|Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore.
authors: I
authors: I
authors: Cutcutache
authors: Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors: W L
authors: WL
authors: Pang
authors: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.|Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
authors: S
authors: S
authors: Thangaraju
authors: Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors: J
authors: J
authors: Ha
authors: Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors: L P
authors: LP
authors: Khoo
authors: Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors: S T
authors: ST
authors: Chin
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors: S
authors: S
authors: Dey
authors: Department of Biomedical Engineering, Duke University, Durham, NC, USA.
authors: G
authors: G
authors: Poore
authors: Department of Pathology, Singapore General Hospital, Singapore, Singapore.
authors: L H C
authors: LH
authors: Tan
authors: Advanced Molecular Pathology Laboratory, Singapore Health Services, Singapore, Singapore.
authors: H K M
authors: HK
authors: Koh
authors: Advanced Molecular Pathology Laboratory, Singapore Health Services, Singapore, Singapore.
authors: K
authors: K
authors: Sabai
authors: Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors: H-L
authors: HL
authors: Rao
authors: Department of Pathology, Tan Tock Seng Hospital, Singapore, Singapore.
authors: K L
authors: KL
authors: Chuah
authors: Department of Pathology, Tan Tock Seng Hospital, Singapore, Singapore.
authors: Y-H
authors: YH
authors: Ho
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.|Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.|Department of Pathology, National University Hospital, National University Health System, Singapore, Singapore.
authors: S-B
authors: SB
authors: Ng
authors: Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan.|Department of Pathology, Taipei Medical University and National Taiwan University, Taipei, Taiwan.
authors: S-S
authors: SS
authors: Chuang
authors: Department of Pathology, Guangdong General Hospital, Guangzhou, China.
authors: F
authors: F
authors: Zhang
authors: Department of Pathology, Guangdong General Hospital, Guangzhou, China.
authors: Y-H
authors: YH
authors: Liu
authors: Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors: T
authors: T
authors: Pongpruttipan
authors: Department of Pathology, Samsung Medical Centre, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors: Y H
authors: YH
authors: Ko
authors: Department of Pathology, University of Malaya, Kuala Lumpur, Malaysia.
authors: P-L
authors: PL
authors: Cheah
authors: Department of Pathology, Hospital Raja Permaisuri Bainun, Ipoh, Malaysia.
authors: N
authors: N
authors: Karim
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.|Department of Haematology-Oncology, National University Hospital, National University Health System, Singapore, Singapore.
authors: W-J
authors: WJ
authors: Chng
authors: Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors: T
authors: T
authors: Tang
authors: Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors: M
authors: M
authors: Tao
authors: Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors: K
authors: K
authors: Tay
authors: Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors: M
authors: M
authors: Farid
authors: Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors: R
authors: R
authors: Quek
authors: Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.|Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore.
authors: S G
authors: SG
authors: Rozen
authors: Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.|Genome Institute of Singapore, A*STAR, Singapore, Singapore.
authors: P
authors: P
authors: Tan
authors: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.|Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.|Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore.
authors: B T
authors: BT
authors: Teh
authors: Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.|Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.|Office of Education, Duke-NUS Medical School, Singapore, Singapore.
authors: S T
authors: ST
authors: Lim
authors: Department of Pathology, Singapore General Hospital, Singapore, Singapore.|Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.|Department of Pathology, National University Hospital, National University Health System, Singapore, Singapore.|Department of Pathology, Guangdong General Hospital, Guangzhou, China.|Department of Pathology, University of Malaya, Kuala Lumpur, Malaysia.|Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore.
authors: S-Y
authors: SY
authors: Tan
authors: Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors: C K
authors: CK
authors: Ong
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D058527:Enteropathy-Associated T-Cell Lymphoma / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D053616:Janus Kinase 3 / Q000235:genetics; D053612:Janus Kinases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D055815:Young Adult
chemical_list: D047428:Protein Kinase Inhibitors; D043562:Receptors, G-Protein-Coupled; D050791:STAT Transcription Factors; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D053616:Janus Kinase 3; D053612:Janus Kinases; C498015:GNAI2 protein, human; D051960:GTP-Binding Protein alpha Subunit, Gi2