TY  - JOUR
A1  - Weißbach, Susann
A1  - Heredia-Guerrero, Sofia Catalina
A1  - Barnsteiner, Stefanie
A1  - Großhans, Lukas
A1  - Bodem, Jochen
A1  - Starz, Hanna
A1  - Langer, Christian
A1  - Appenzeller, Silke
A1  - Knop, Stefan
A1  - Steinbrunn, Torsten
A1  - Rost, Simone
A1  - Einsele, Hermann
A1  - Bargou, Ralf Christian
A1  - Rosenwald, Andreas
A1  - Stühmer, Thorsten
A1  - Leich, Ellen
T1  - Exon-4 Mutations in KRAS Affect MEK/ERK and PI3K/AKT Signaling in Human Multiple Myeloma Cell Lines
JF  - Cancers
N2  - Approximately 20% of multiple myeloma (MM) cases harbor a point mutation in KRAS. However, there is still no final consent on whether KRAS-mutations are associated with disease outcome. Specifically, no data exist on whether KRAS-mutations have an impact on survival of MM patients at diagnosis in the era of novel agents. Direct blockade of KRAS for therapeutic purposes is mostly impossible, but recently a mutation-specific covalent inhibitor targeting KRAS\(^{p.G12C}\) entered into clinical trials. However, other KRAS hotspot-mutations exist in MM patients, including the less common exon-4 mutations. For the current study, the coding regions of KRAS were deep-sequenced in 80 newly diagnosed MM patients, uniformely treated with three cycles of bortezomib plus dexamethasone and cyclophosphamide (VCD)-induction, followed by high-dose chemotherapy and autologous stem cell transplantation. Moreover, the functional impact of KRAS\(^{p.G12A}\) and the exon-4 mutations p.A146T and p.A146V on different survival pathways was investigated. Specifically, KRAS\(^{WT}\), KRAS\(^{p.G12A}\), KRAS\(^{p.A146T}\), and KRAS\(^{p.A146V}\) were overexpressed in HEK293 cells and the KRAS\(^{WT}\) MM cell lines JJN3 and OPM2 using lentiviral transduction and the Sleeping Beauty vector system. Even though KRAS-mutations were not correlated with survival, all KRAS-mutants were found capable of potentially activating MEK/ERK- and sustaining PI3K/AKT-signaling in MM cells.
KW  - multiple myeloma
KW  - KRAS
KW  - MEK/ERK-signaling
KW  - AKT-signaling
KW  - amplicon sequencing
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200617
SN  - 2072-6694
VL  - 12
IS  - 2
ER  - 
TY  - JOUR
A1  - Kolokotronis, Konstantinos
A1  - Pluta, Natalie
A1  - Klopocki, Eva
A1  - Kunstmann, Erdmute
A1  - Messroghli, Daniel
A1  - Maack, Christoph
A1  - Tejman-Yarden, Shai
A1  - Arad, Michael
A1  - Rost, Simone
A1  - Gerull, Brenda
T1  - New Insights on Genetic Diagnostics in Cardiomyopathy and Arrhythmia Patients Gained by Stepwise Exome Data Analysis
JF  - Journal of Clinical Medicine
N2  - Inherited cardiomyopathies are characterized by clinical and genetic heterogeneity that challenge genetic diagnostics. In this study, we examined the diagnostic benefit of exome data compared to targeted gene panel analyses, and we propose new candidate genes. We performed exome sequencing in a cohort of 61 consecutive patients with a diagnosis of cardiomyopathy or primary arrhythmia, and we analyzed the data following a stepwise approach. Overall, in 64% of patients, a variant of interest (VOI) was detected. The detection rate in the main sub-cohort consisting of patients with dilated cardiomyopathy (DCM) was much higher than previously reported (25/36; 69%). The majority of VOIs were found in disease-specific panels, while a further analysis of an extended panel and exome data led to an additional diagnostic yield of 13% and 5%, respectively. Exome data analysis also detected variants in candidate genes whose functional profile suggested a probable pathogenetic role, the strongest candidate being a truncating variant in STK38. In conclusion, although the diagnostic yield of gene panels is acceptable for routine diagnostics, the genetic heterogeneity of cardiomyopathies and the presence of still-unknown causes favor exome sequencing, which enables the detection of interesting phenotype–genotype correlations, as well as the identification of novel candidate genes.
KW  - cardiomyopathy
KW  - cardiogenetics
KW  - whole exome sequencing
KW  - targeted gene panel
KW  - candidate genes
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236094
VL  - 9
IS  - 7
ER  -