دورية أكاديمية
Integrated genomic analyses of cutaneous T-cell lymphomas reveal the molecular bases for disease heterogeneity.
| العنوان: | Integrated genomic analyses of cutaneous T-cell lymphomas reveal the molecular bases for disease heterogeneity. |
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| المؤلفون: | Park J; Department of Dermatology, and.; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL., Daniels J; Department of Dermatology, and.; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL., Wartewig T; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany.; Center for Translational Cancer Research (TranslaTUM), Munich, Germany., Ringbloom KG; Department of Dermatology, and.; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL., Martinez-Escala ME; Department of Dermatology, and., Choi S; Department of Dermatology, and., Thomas JJ; Department of Dermatology, and.; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL., Doukas PG; Department of Dermatology, and., Yang J; Department of Dermatology, and.; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL., Snowden C; Department of Dermatology, and.; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL., Law C; Department of Dermatology, and.; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL., Lee Y; Department of Dermatology, and.; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL., Lee K; Department of Dermatology, and.; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL., Zhang Y; Department of Dermatology, and.; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL., Conran C; Department of Dermatology, and., Tegtmeyer K; Department of Dermatology, and.; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL., Mo SH; Department of Dermatology, and.; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL., Pease DR; Department of Dermatology, and., Jothishankar B; Department of Medicine, Section of Dermatology, University of Chicago Pritzker School of Medicine, Chicago, IL., Kwok PY; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA., Abdulla FR; Division of Dermatology, City of Hope Comprehensive Cancer Center, Duarte, CA., Pro B; Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL., Louissaint A; Department of Pathology, Massachusetts General Hospital, Boston, MA., Boggon TJ; Department of Pharmacology and.; Department of Molecular Biology and Biophysics, Yale University School of Medicine, New Haven, CT., Sosman J; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL., Guitart J; Department of Dermatology, and., Rao D; Division of Rheumatology, Inflammation, Immunity, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Ruland J; Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany.; Center for Translational Cancer Research (TranslaTUM), Munich, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany; and.; German Center for Infection Research (DZIF), Munich, Germany., Choi J; Department of Dermatology, and.; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL.; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL. |
| المصدر: | Blood [Blood] 2021 Oct 07; Vol. 138 (14), pp. 1225-1236. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York] : Elsevier Original Publication: New York, Grune & Stratton [etc.] |
| مواضيع طبية MeSH: | Transcriptome*, Lymphoma, T-Cell, Cutaneous/*genetics, Animals ; Cells, Cultured ; Forkhead Box Protein M1/genetics ; Gene Expression Regulation, Neoplastic ; Genes, Tumor Suppressor ; Humans ; Mice ; Mutation ; Oncogenes ; Tumor Suppressor Protein p53/genetics |
| مستخلص: | Cutaneous T-cell lymphomas (CTCLs) are a clinically heterogeneous collection of lymphomas of the skin-homing T cell. To identify molecular drivers of disease phenotypes, we assembled representative samples of CTCLs from patients with diverse disease subtypes and stages. Via DNA/RNA-sequencing, immunophenotyping, and ex vivo functional assays, we identified the landscape of putative driver genes, elucidated genetic relationships between CTCLs across disease stages, and inferred molecular subtypes in patients with stage-matched leukemic disease. Collectively, our analysis identified 86 putative driver genes, including 19 genes not previously implicated in this disease. Two mutations have never been described in any cancer. Functionally, multiple mutations augment T-cell receptor-dependent proliferation, highlighting the importance of this pathway in lymphomagenesis. To identify putative genetic causes of disease heterogeneity, we examined the distribution of driver genes across clinical cohorts. There are broad similarities across disease stages. Many driver genes are shared by mycosis fungoides (MF) and Sezary syndrome (SS). However, there are significantly more structural variants in leukemic disease, leading to highly recurrent deletions of putative tumor suppressors that are uncommon in early-stage skin-centered MF. For example, TP53 is deleted in 7% and 87% of MF and SS, respectively. In both human and mouse samples, PD1 mutations drive aggressive behavior. PD1 wild-type lymphomas show features of T-cell exhaustion. PD1 deletions are sufficient to reverse the exhaustion phenotype, promote a FOXM1-driven transcriptional signature, and predict significantly worse survival. Collectively, our findings clarify CTCL genetics and provide novel insights into pathways that drive diverse disease phenotypes. (© 2021 by The American Society of Hematology.) |
| التعليقات: | Comment in: Blood. 2021 Oct 7;138(14):1201-1203. (PMID: 34618002) |
| References: | Cancer Cell. 2018 Apr 9;33(4):547-562. (PMID: 29634943) Bioinformatics. 2010 Oct 1;26(19):2438-44. (PMID: 20709693) Cell. 2018 Dec 13;175(7):1958-1971.e15. (PMID: 30449619) Nat Commun. 2020 Apr 14;11(1):1806. (PMID: 32286303) Blood. 2017 Sep 21;130(12):1430-1440. (PMID: 28694326) Blood. 2019 Jun 27;133(26):2776-2789. (PMID: 31101622) Nat Genet. 2015 Dec;47(12):1465-70. (PMID: 26551667) BMC Bioinformatics. 2013 Jan 16;14:7. (PMID: 23323831) Blood. 2010 Aug 5;116(5):767-71. (PMID: 20484084) Nat Immunol. 2016 Jul;17(7):851-860. (PMID: 27158840) Blood. 2014 Mar 27;123(13):2034-43. (PMID: 24497536) Proc Natl Acad Sci U S A. 2015 Apr 28;112(17):5473-8. (PMID: 25827230) Sci Rep. 2021 Feb 17;11(1):3962. (PMID: 33597573) PLoS Pathog. 2015 Oct 20;11(10):e1005177. (PMID: 26485519) Sci Immunol. 2019 Jul 5;4(37):. (PMID: 31278120) J Exp Med. 2001 Dec 17;194(12):1711-9. (PMID: 11748273) Blood Adv. 2019 Feb 26;3(4):519-530. (PMID: 30770361) Annu Rev Immunol. 2019 Apr 26;37:457-495. (PMID: 30676822) Genome Biol. 2011;12(4):R41. (PMID: 21527027) Nature. 2014 Jan 23;505(7484):495-501. (PMID: 24390350) Cancer Cell. 2017 Jul 10;32(1):27-41.e4. (PMID: 28625481) Nature. 2017 Feb 1;542(7639):110-114. (PMID: 28150777) Nature. 2017 Dec 7;552(7683):121-125. (PMID: 29143824) G Ital Dermatol Venereol. 2012 Dec;147(6):523-31. (PMID: 23149698) J Clin Oncol. 2010 Nov 1;28(31):4730-9. (PMID: 20855822) N Engl J Med. 2015 Nov 12;373(20):1926-36. (PMID: 26559571) Genome Biol. 2010;11(10):R106. (PMID: 20979621) Nat Genet. 2015 Dec;47(12):1426-34. (PMID: 26551670) Cancer Immunol Res. 2018 Aug;6(8):900-909. (PMID: 29895574) Cell. 2015 Jul 2;162(1):184-97. (PMID: 26095251) J Exp Med. 2010 May 10;207(5):1031-44. (PMID: 20439541) Nat Rev Cancer. 2007 Nov;7(11):847-59. (PMID: 17943136) Trends Immunol. 2019 May;40(5):403-414. (PMID: 30979616) Mod Pathol. 2013 Jan;26(1):32-43. (PMID: 22918164) Sci Transl Med. 2018 May 9;10(440):. (PMID: 29743350) Nat Genet. 2015 Sep;47(9):1011-9. (PMID: 26192916) Blood. 2005 May 15;105(10):3768-85. (PMID: 15692063) Blood. 2014 May 8;123(19):2915-23. (PMID: 24632715) Nat Rev Cancer. 2020 Apr;20(4):218-232. (PMID: 32024970) Curr Treat Options Oncol. 2016 Jul;17(7):33. (PMID: 27262707) Nat Immunol. 2019 Aug;20(8):1059-1070. (PMID: 31308541) Nat Genet. 2015 Sep;47(9):1056-60. (PMID: 26258847) Am J Clin Pathol. 2011 Dec;136(6):944-53. (PMID: 22095381) Nat Genet. 2015 Nov;47(11):1304-15. (PMID: 26437031) |
| معلومات مُعتمدة: | F30 CA265107 United States CA NCI NIH HHS; 2019092 United States DDCF Doris Duke Charitable Foundation; P30 AR070253 United States AR NIAMS NIH HHS; DP2 AI136599 United States AI NIAID NIH HHS; K08 AR072791 United States AR NIAMS NIH HHS; P30 AR075049 United States AR NIAMS NIH HHS; K08 CA191019 United States CA NCI NIH HHS; T32 CA009560 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Forkhead Box Protein M1) 0 (TP53 protein, human) 0 (Tumor Suppressor Protein p53) |
| تواريخ الأحداث: | Date Created: 20210611 Date Completed: 20211206 Latest Revision: 20240207 |
| رمز التحديث: | 20240207 |
| مُعرف محوري في PubMed: | PMC8499046 |
| DOI: | 10.1182/blood.2020009655 |
| PMID: | 34115827 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1528-0020 |
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| DOI: | 10.1182/blood.2020009655 |