Browsing by Author "P. Tan"

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    JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma
    (2016-06-01) M. L. Nairismägi; J. Tan; J. Q. Lim; S. Nagarajan; C. C.Y. Ng; V. Rajasegaran; D. Huang; W. K. Lim; Y. Laurensia; G. C. Wijaya; Z. M. Li; I. Cutcutache; W. L. Pang; S. Thangaraju; J. Ha; L. P. Khoo; S. T. Chin; S. Dey; G. Poore; L. H.C. Tan; H. K.M. Koh; K. Sabai; H. L. Rao; K. L. Chuah; Y. H. Ho; S. B. Ng; S. S. Chuang; F. Zhang; Y. H. Liu; T. Pongpruttipan; Y. H. Ko; P. L. Cheah; N. Karim; W. J. Chng; T. Tang; M. Tao; K. Tay; M. Farid; R. Quek; S. G. Rozen; P. Tan; B. T. Teh; S. T. Lim; S. Y. Tan; C. K. Ong; National Cancer Centre, Singapore; Duke-NUS Medical School Singapore; Cancer Science Institute of Singapore; Duke University; Singapore General Hospital; Singapore Health Services; Sun Yat-Sen University Cancer Center; Tan Tock Seng Hospital; Yong Loo Lin School of Medicine; Chi Mei Medical Center; Taipei Medical University; Guangdong General Hospital; Mahidol University; SungKyunKwan University, School of Medicine; University of Malaya; Hospital Raja Permaisuri Bainun; National University Hospital, Singapore; A-Star, Genome Institute of Singapore; A-Star, Institute of Molecular and Cell Biology
    © 2016 Macmillan Publishers Limited. 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 .

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