TY  - JOUR
A1  - Leich, E.
A1  - Weißbach, S.
A1  - Klein, H.-U.
A1  - Grieb, T.
A1  - Pischimarov, J.
A1  - Stühmer, T.
A1  - Chatterjee, M.
A1  - Steinbrunn, T.
A1  - Langer, C.
A1  - Eilers, M.
A1  - Knop, S.
A1  - Einsele, H.
A1  - Bargou, R.
A1  - Rosenwald, A.
T1  - Multiple myeloma is affected by multiple and heterogeneous somatic mutations in adhesion- and receptor tyrosine kinase signaling molecules
JF  - Blood Cancer Journal
N2  - Multiple myeloma (MM) is a largely incurable plasma cell malignancy with a poorly understood and heterogeneous clinical course. To identify potential, functionally relevant somatic mutations in MM, we performed whole-exome sequencing of five primary MM, corresponding germline DNA and six MM cell lines, and developed a bioinformatics strategy that also integrated published mutational data of 38 MM patients. Our analysis confirms that identical, recurrent mutations of single genes are infrequent in MM, but highlights that mutations cluster in important cellular pathways. Specifically, we show enrichment of mutations in adhesion molecules of MM cells, emphasizing the important role for the interaction of the MM cells with their microenvironment. We describe an increased rate of mutations in receptor tyrosine kinases (RTKs) and associated signaling effectors, for example, in EGFR, ERBB3, KRAS and MAP2K2, pointing to a role of aberrant RTK signaling in the development or progression of MM. The diversity of mutations affecting different nodes of a particular signaling network appears to be an intrinsic feature of individual MM samples, and the elucidation of intra- as well as interindividual redundancy in mutations that affect survival pathways will help to better tailor targeted therapeutic strategies to the specific needs of the MM patient.
KW  - multiple myeloma
KW  - somatic mutations
KW  - whole-exome sequencing
KW  - adhesion
KW  - receptor tyrosine kinases
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128663
VL  - 3
IS  - e102
ER  - 
TY  - JOUR
A1  - Maurus, K.
A1  - Kosnopfel, C.
A1  - Kneitz, H.
A1  - Appenzeller, S.
A1  - Schrama, D.
A1  - Glutsch, V.
A1  - Roth, S.
A1  - Gerhard-Hartmann, E.
A1  - Rosenfeldt, M.
A1  - Möhrmann, L.
A1  - Fröhlich, M.
A1  - Hübschmann, D.
A1  - Stenzinger, A.
A1  - Glimm, H.
A1  - Fröhling, S.
A1  - Goebeler, M.
A1  - Rosenwald, A.
A1  - Kutzner, H.
A1  - Schilling, B.
T1  - Cutaneous epithelioid haemangiomas show somatic mutations in the mitogen-activated protein kinase pathway
JF  - British Journal of Dermatology
N2  - Background
Epithelioid haemangioma (EH) arising from the skin is a benign vascular tumour with marked inflammatory cell infiltration, which exhibits a high tendency to persist and frequently recurs after resection. So far, the underlying pathogenesis is largely elusive.

Objectives
To identify genetic alterations by next-generation sequencing and/or droplet digital polymerase chain reaction (ddPCR) in cutaneous EH.

Methods
DNA and RNA from an EH lesion of an index patient were subjected to whole-genome and RNA sequencing. Multiplex PCR-based panel sequencing of genomic DNA isolated from archival formalin-fixed paraffin-embedded tissue of 18 patients with cutaneous EH was performed. ddPCR was used to confirm mutations.

Results
We identified somatic mutations in genes of the mitogen-activated protein kinase (MAPK) pathway (MAP2K1 and KRAS) in cutaneous EH biopsies. By ddPCR we could confirm the recurrent presence of activating, low-frequency mutations affecting MAP2K1. In total, nine out of 18 patients analysed showed activating MAPK pathway mutations, which were mutually exclusive. Comparative analysis of tissue areas enriched for lymphatic infiltrate or aberrant endothelial cells, respectively, revealed an association of these mutations with the presence of endothelial cells.

Conclusions
Taken together, our data suggest that EH shows somatic mutations in genes of the MAPK pathway which might contribute to the formation of this benign tumour.
KW  - protein kinase pathway
KW  - Background Epithelioid haemangioma
KW  - somatic mutations
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258333
VL  - 186
IS  - 3
ER  -