TY  - JOUR
A1  - Weis, Eva
A1  - Schoen, Holger
A1  - Victor, Anja
A1  - Spix, Claudia
A1  - Ludwig, Marco
A1  - Schneider-Raetzke, Brigitte
A1  - Kohlschmidt, Nicolai
A1  - Bartsch, Oliver
A1  - Gerhold-Ay, Aslihan
A1  - Boehm, Nils
A1  - Grus, Franz
A1  - Haaf, Thomas
A1  - Galetzka, Danuta
T1  - Reduced mRNA and Protein Expression of the Genomic Caretaker RAD9A in Primary Fibroblasts of Individuals with Childhood and Independent Second Cancer
JF  - PLoS ONE
N2  - Background: 

The etiology of secondary cancer in childhood cancer survivors is largely unclear. Exposure of normal somatic cells to radiation and/or chemotherapy can damage DNA and if not all DNA lesions are properly fixed, the mis-repair may lead to pathological consequences. It is plausible to assume that genetic differences, i.e. in the pathways responsible for cell cycle control and DNA repair, play a critical role in the development of secondary cancer. 

Methodology/Findings: 

To identify factors that may influence the susceptibility for second cancer formation, we recruited 20 individuals who survived a childhood malignancy and then developed a second cancer as well as 20 carefully matched control individuals with childhood malignancy but without a second cancer. By antibody microarrays, we screened primary fibroblasts of matched patients for differences in the amount of representative DNA repair-associated proteins. We found constitutively decreased levels of RAD9A and several other DNA repair proteins in two-cancer patients, compared to one-cancer patients. The RAD9A protein level increased in response to DNA damage, however to a lesser extent in the two-cancer patients. Quantification of mRNA expression by real-time RT PCR revealed lower RAD9A mRNA levels in both untreated and 1 Gy gamma-irradiated cells of two-cancer patients. 

Conclusions/Significance: 

Collectively, our results support the idea that modulation of RAD9A and other cell cycle arrest and DNA repair proteins contribute to the risk of developing a second malignancy in childhood cancer patients.
KW  - DNA methylation
KW  - Malignant neoplasms
KW  - Genes
KW  - Instability
KW  - Stability
KW  - Susceptibility
KW  - Checkpoints
KW  - Repair
KW  - Damage
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-141838
VL  - 6
IS  - 10
ER  - 
TY  - JOUR
A1  - Carmela Vegliante, Maria
A1  - Royo, Cristina
A1  - Palomero, Jara
A1  - Salaverria, Itziar
A1  - Balint, Balazs
A1  - Martin-Guerrero, Idoia
A1  - Agirre, Xabier
A1  - Lujambio, Amaia
A1  - Richter, Julia
A1  - Xargay-Torrent, Silvia
A1  - Bea, Silvia
A1  - Hernandez, Luis
A1  - Enjuanes, Anna
A1  - Jose Calasanz, Maria
A1  - Rosenwald, Andreas
A1  - Ott, German
A1  - Roman-Gomez, Jose
A1  - Prosper, Felipe
A1  - Esteller, Manel
A1  - Jares, Pedro
A1  - Siebert, Reiner
A1  - Campo, Elias
A1  - Martin-Subero, Jose I.
A1  - Amador, Virginia
T1  - Epigenetic Activation of SOX11 in Lymphoid Neoplasms by Histone Modifications
JF  - PLoS ONE
N2  - Recent studies have shown aberrant expression of SOX11 in various types of aggressive B-cell neoplasms. To elucidate the molecular mechanisms leading to such deregulation, we performed a comprehensive SOX11 gene expression and epigenetic study in stem cells, normal hematopoietic cells and different lymphoid neoplasms. We observed that SOX11 expression is associated with unmethylated DNA and presence of activating histone marks (H3K9/14Ac and H3K4me3) in embryonic stem cells and some aggressive B-cell neoplasms. In contrast, adult stem cells, normal hematopoietic cells and other lymphoid neoplasms do not express SOX11. Such repression was associated with silencing histone marks H3K9me2 and H3K27me3. The SOX11 promoter of non-malignant cells was consistently unmethylated whereas lymphoid neoplasms with silenced SOX11 tended to acquire DNA hypermethylation. SOX11 silencing in cell lines was reversed by the histone deacetylase inhibitor SAHA but not by the DNA methyltransferase inhibitor AZA. These data indicate that, although DNA hypermethylation of SOX11 is frequent in lymphoid neoplasms, it seems to be functionally inert, as SOX11 is already silenced in the hematopoietic system. In contrast, the pathogenic role of SOX11 is associated with its de novo expression in some aggressive lymphoid malignancies, which is mediated by a shift from inactivating to activating histone modifications.
KW  - Mantle cell lymphoma
KW  - Defined burkitts lymphoma
KW  - Transcription-factor
KW  - Gene-expression
KW  - High-resolution
KW  - DNA methylation
KW  - Nuclear expression
KW  - Cancer
KW  - Microarray
KW  - Survival
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135325
VL  - 6
IS  - 6
ER  -