Kunz, Manfred, Loeffler-Wirth, Henry, Dannemann, Michael, Willscher, Edith, Doose, Gero, Kelso, Janet, Kottek, Tina, Nickel, Birgit, Hopp, Lydia, Landsberg, Jenny, Hoffmann, Steve, Tueting, Thomas, Zigrino, Paola ORCID: 0000-0002-7470-0064, Mauch, Cornelia, Utikal, Jochen ORCID: 0000-0001-5316-0241, Ziemer, Mirjana, Schulze, Hans-Joachim, Holzel, Michael, Roesch, Alexander, Kneitz, Susanne, Meierjohann, Svenja, Bosserhoff, Anja, Binder, Hans and Schartl, Manfred (2018). RNA-seq analysis identifies different transcriptomic types and developmental trajectories of primary melanomas. Oncogene, 37 (47). S. 6136 - 6152. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5594

Full text not available from this repository.

Abstract

Recent studies revealed trajectories of mutational events in early melanomagenesis, but the accompanying changes in gene expression are far less understood. Therefore, we performed a comprehensive RNA-seq analysis of laser-microdissected melanocytic nevi (n = 23) and primary melanoma samples (n = 57) and characterized the molecular mechanisms of early melanoma development. Using self-organizing maps, unsupervised clustering, and analysis of pseudotime (PT) dynamics to identify evolutionary trajectories, we describe here two transcriptomic types of melanocytic nevi (N1 and N2) and primary melanomas (M1 and M2). N1/M1 lesions are characterized by pigmentation-type and MITF gene signatures, and a high prevalence of NRAS mutations in M1 melanomas. N2/M2 lesions are characterized by inflammatory-type and AXL gene signatures with an equal distribution of wild-type and mutated BRAF and low prevalence of NRAS mutations in M2 melanomas. Interestingly, N1 nevi and M1 melanomas and N2 nevi and M2 melanomas, respectively, cluster together, but there is no clustering in a stage-dependent manner. Transcriptional signatures of M1 melanomas harbor signatures of BRAF/MEK inhibitor resistance and M2 melanomas harbor signatures of anti-PD-1 antibody treatment resistance. Pseudotime dynamics of nevus and melanoma samples are suggestive for a switch-like immune-escape mechanism in melanoma development with downregulation of immune genes paralleled by an increasing expression of a cell cycle signature in late-stage melanomas. Taken together, the transcriptome analysis identifies gene signatures and mechanisms underlying development of melanoma in early and late stages with relevance for diagnostics and therapy.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Kunz, ManfredUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loeffler-Wirth, HenryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dannemann, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Willscher, EdithUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doose, GeroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kelso, JanetUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kottek, TinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nickel, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hopp, LydiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Landsberg, JennyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoffmann, SteveUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tueting, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zigrino, PaolaUNSPECIFIEDorcid.org/0000-0002-7470-0064UNSPECIFIED
Mauch, CorneliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Utikal, JochenUNSPECIFIEDorcid.org/0000-0001-5316-0241UNSPECIFIED
Ziemer, MirjanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulze, Hans-JoachimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holzel, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roesch, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kneitz, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meierjohann, SvenjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bosserhoff, AnjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Binder, HansUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schartl, ManfredUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-165447
DOI: 10.1038/s41388-018-0385-y
Journal or Publication Title: Oncogene
Volume: 37
Number: 47
Page Range: S. 6136 - 6152
Date: 2018
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1476-5594
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENE-EXPRESSION SIGNATURE; METASTATIC MELANOMA; CUTANEOUS MELANOMA; PROGRESSION; VALIDATION; EVOLUTION; THICKNESS; THERAPYMultiple languages
Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/16544

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item