Research Unit

microRNAs predict recurrence risk of head and neck tumors (2018)

miRNAs predict the course of HPV-negative head and neck cancer after radiation chemotherapy.

Please find here the detailed press information

Original Publication
Hess, J. et al. (2018): A Five-MicroRNA Signature Predicts Survival and Disease Control of Patients with Head and Neck Cancer Negative for HPV-infection. Clinical Cancer Research, DOI: 10.1158/1078-0432.CCR-18-0776


FancA (Fanconi anemia) gene amplification and overexpression crucial for radiotherapeutic failure in head and neck cancers (2017)

In vitro analysis of the effects of the FancA (Fanconi anemia) gene expression on radiation sensitivity confirmed previous finding (Bauer et al. 2008) of association of gain on 16q23-24 with FancA and correlation with reduced progression-free survival after radiotherapy.

Original Publication
Hess, J. ; Unger, K. ; Orth, M. ; Schötz, U. ; Schüttrumpf, L. ; Zangen, V. ; Gimenez-Aznar, I. ; Michna, A. ; Schneider, L. ; Stamp, R. ; Selmansberger, M. ; Braselmann, H. ; Hieber, L. ; Drexler, G.A. ; Kuger, S. ; Klein, D. ; Jendrossek, V. ; Friedl, A.A. ; Belka, C. ; Zitzelsberger, H. ; Lauber, K. Genomic amplification of Fanconi anemia complementation group A (FancA) in head and neck squamous cell carcinoma (HNSCC): Cellular mechanisms of radioresistance and clinical relevance. Cancer Lett. 386, 87-99 (2017) PubMed

microRNAs help to predict disease progression in brain tumors (2016)

New method of predicting disease progression in gliobastoma patients who have undergone standard treatment.

Original publication:

Maximilian Niyazi, Adriana Pitea, Michel Mittelbronn, Joachim Steinbach, Carsten Sticht, Franz Zehentmayr, Daniel Piehlmaier, Horst Zitzelsberger, Ute Ganswindt, Claus Rödel, Kirsten Lauber, Claus Belka, Kristian Unger (2016). A 4-miRNA signature predicts the therapeutic outcome of glioblastoma, Oncotarget, doi: 10.18632/oncotarget.994

Thyroid carcinoma: Biomarker reveals cancer cause (2014)

The expression of the protein CLIP2 provides information on whether a papillary thyroid carcinoma was induced by radiation or had a sporadic origin.

Original publication

M Selmansberger, A Feuchtinger, L Zurnadzhy, A Michna, J C Kaiser, M Abend, A Brenner, T Bogdanova, A Walch, K Unger, H Zitzelsberger and J Hess (2014). CLIP2 as radiation biomarker in papillary thyroid carcinoma, Oncogene. PubMed

Evolution of optical window fluorescent protein variants under selective pressure (2014)

Amrose was evolved to have high excitation at 633 nm and excitation/emission into the far-red optical window, which is optimal for whole-body and deep tissue imaging as demonstrated in the zebrafish and mouse model.

Publication:
Schoetz, U. et al. (2014).  Usefulness of a Darwinian system in a biotechnological application: evolution of optical window fluorescent protein variants under selective pressure, PLOS ONE, doi: 10.1371/journal.pone.0107069

Genetic marker for radiation associated thyroid cancer (2011)

Gain of chromosome band 7q11 in papillary thyroid carcinomas of young patients is associated with exposure to low-dose irradiation

Ionizing radiation is a major known risk factor in thyroid cancer which is the most frequent cancer of the human endocrine system. The main consequence of the Chernobyl accident has been an increase in papillary thyroid carcinomas (PTCs) in those exposed to radioactive fallout as young children. Our aim was to identify genomic alterations that are associated with exposure to radiation.

We used array CGH to analyse a main (n=52) and a validation cohort (n=28) of PTC from patients aged under 25 at operation and matched for age at diagnosis and residency. Both cohorts consisted of patients exposed and not exposed to radioiodine fallout. The study showed association of a gain on chromosome 7 (7q11.22-11.23) with exposure (false discovery rate =0.035). 39% from the exposed group and no case from the unexposed group showed the alteration. This was confirmed in the validation set. Because only a subgroup of cases in the exposed groups showed gain of 7q11.22-11.23 it is likely that different molecular subgroups and routes of radiation-induced carcinogenesis exist. The candidate gene CLIP2 was specifically overexpressed in the exposed cases. In addition, the expression of the genes PMS2L11, PMS2L3, and STAG3L3 correlated with gain of 7q11.22-11.23. An enrichment of the gene ontology terms ’DNA repair’ (PMS2L3, PMS2L5), ’response to DNA damage stimulus’ (BAZ1B, PMS2L3, PMS2L5, RFC2), and ’cell-cell adhesion’ (CLDN3, CLDN4) was found.

This is the first study on post-Chernobyl PTC that uses appropriately matched exposed and unexposed cohorts and provides novel insights into the radiation-related carcinogenesis of young onset PTC and, with the exposure-specific gain of 7q11 and overexpression of the CLIP2 gene, novel radiation-specific molecular markers.

Please finde here slides illustrating the highlight

Contact persons: Prof. Dr. Horst Zitzelsberger  Dr. Kristian Unger , Julia Heß

Publication

  • Hess, J., Thomas, G., Braselmann, H., Bauer, V., Bogdanova, T., Wienberg, J., Zitzelsberger, H. and Unger, K. (2011)
    Gain of chromosome band 7q11 in papillary thyroid carcinomas of young patients is associated with exposure to low-dose irradiation. Proc Natl Acad Sci U S A Epub ahead of print

Press Release

Translocation analysis identifies individuals with a potentially elevated radiation sensitivity (2011)

Background
Radiotherapists are highly interested in optimizing doses especially for patients who tend to suffer from side effects of radiotherapy (RT). It seems to be helpful to identify radiosensitive individuals before RT. Thus we examined aberrations in FISH painted chromosomes in in vitro irradiated blood samples of a group of 47 patients suffering from breast cancer. In parallel, a follow-up of side effects in these patients was registered and compared to detected chromosome aberrations.

Methods
Blood samples (taken before radiotherapy) were irradiated in vitro with 3 Gy X-rays and analysed by FISH-painting to obtain aberration frequencies of first cycle metaphases for each patient. Aberration frequencies were analysed statistically to identify individuals with an elevated or reduced radiation response. Clinical data of patients have been recorded in parallel to gain knowledge on acute side effects of radiotherapy.

Results
Eight patients with a significantly elevated or reduced aberration yield were identified by use of a t-test criterion. A comparison with clinical side effects revealed that among patients with elevated aberration yields one exhibited a higher degree of acute toxicity and two patients a premature onset of skin reaction already after a cumulative dose of only 10 Gy. A significant relationship existed between translocations in vitro and the time dependent occurrence of side effects of the skin during the therapy period.

Conclusions
The results suggest that translocations can be used as a test to identify individuals with a potentially elevated radiosensitivity.

Contact persons: Prof. Dr. Horst Zitzelsberger  , Reinhard Huber , Herbert Braselmann

Publication

  • Huber, R., Braselmann, H., Geinitz, H., Jaehnert, I., Baumgartner, A., Thamm, R., Figel, M., Molls, M. and
    Zitzelsberger, H
    . Chromosomal radiosensitivity and acute radiation side effects after radiotherapy in tumour patients - a follow-up study. Radiat Oncol. 2011 6, 32 Open access

Novel gene rearrangements in radiation-transformed breast cells identified by high-resolution breakpoint analysis of chromosomal aberrations (2010)

Novel gene rearrangements in radiation-transformed breast cells identified by high-resolution breakpoint analysis of chromosomal aberrations


Chromosomal copy number alterations and chromosomal rearrangements are frequent mutations in human tumours. In breast cancer, in particular, nothing was known about the role of gene rearrangements. With a high resolution (1Mb) BAC-array study in radiation-transformed breast cells we identified a series of chromosome rearrangements involving chromosome 7, 8, 10 and 12. By narrowing down the breakpoints with FISH analysis using BAC clones from a 32k library, we identified the genes Has2, Grid1, Ret, Cpm, Tbx3, Tbx5, Tuba1a, Wnt1 and Arf3 in the rearranged regions. The RNA expression of all genes is deregulated except of Tbx5 and Tbx3. Since the gene rearrangements occurred in the radiation-transformed and tumourigenic cell lines only, it is likely that these were generated in conjunction with malignant transformation of the epithelial breast cells. Therefore, this might reflect an early molecular event in breast carcinogenesis. In a preliminary study, the same gene alterations are also found in sporadic breast cancer tissues, thus, these rearrangements could probably serve as biological markers for breast cancer. This will be proven in a further study of breast tumours tissues.

Please finde here slides illustrating the highlight

Contact persons: Prof. Dr. Horst Zitzelsberger  , Dr. Kristian Unger

Publication

  • Unger K, Wienberg J, Riches A, Hieber L, Walch A, Brown A, O’Brien PCM, Briscoe C, Gray L, Rodriguez E, Jackl G, et al., Novel gene rearrangements in transformed breast cells identified by high-resolution breakpoint analysis of chromosomal aberrations. Endocrine-Related Cancer 2010, 17, 87-96

Characteristic genomic copy number alterations in human papillary thyroid carcinomas governed by rearrangements of the RET oncogene (2008)

Characteristic genomic copy number changes in human papillary thyroid carcinomas governed by rearrangements of the RET oncogene

Thyroid cancer is the most frequent cancer of the endocrine system in humans. Despite widespread use of multimodality treatment, survival rates have not improved very much, which suggests that new treatment options should be explored. Therefore, in papillary thyroid cancer tyrosine kinase inhibitors are being studied in clinical trials because these tumours are well characterized for gene alterations along the MAP kinase pathway, like RET rearrangements (RET/PTC). However, it is unclear whether additional alterations or alternative routes of tumour development exist.

To address this question we applied array-based comparative genomic hybridization (array CGH) to papillary thyroid carcinomas with known status of RET/PTC. Principal component analysis and hierarchical cluster analysis identified cases with similar aberration patterns. Significant deviations between tumour-groups with different RET status were obtained by statistical testing revealing specific aberration signatures that discriminate between RET/PTC-positive and RET/PTC-negative cases.

There are additional alterations in RET/PTC-positive tumours which may act as modifiers of RET activation. In contrast, alterations in RET/PTC-negative tumours indicate alternative routes of tumour development. Based on these data several candidate genes were identified supporting the idea that the MAP kinase pathway is linked to a network of other pathways in thyroid tumourigenesis of which the apoptosis and the PI3K pathways are most prominent.

These findings may lead to the identification of new therapeutic targets in papillary thyroid cancer.

Please finde here slides illustrating the highlight

Contact persons: Prof. Dr. Horst Zitzelsberger , Dr. Kristian Unger

Publication

  • Unger, K., Malisch, E., Thomas, G., Braselmann, H., Walch, A., Jackl, G., Lewis, P., Lengfelder, E., Bogdanova, T., Wienberg, J. et al. (2008) Array CGH demonstrates characteristic aberration signatures in human papillary thyroid carcinomas governed by RET/PTC.  Oncogene. 27, 4592-602

Chromosomal changes characterize head and neck cancer with poor prognosis after radiotherapy (2008)

Chromosomal changes characterize head and neck cancer with poor prognosis after radiotherapy

Head and neck squamous cell carcinoma (HNSCC) represents the seventh most common cancer disease. Radiotherapy is an important strategy in the treatment of HNSCC, however, disease control by radiotherapy is impaired in subgroup of cancers. Since it is well established that genetic alterations may be associated to prognosis in tumour patients we investigated chromosomal changes that predict the clinical outcome of HNSCC after radiotherapy. We applied comparative genomic hybridization to tissue samples from HNSCC patients scheduled for radiotherapy. Genomic aberrations were studied for their impact on locoregional progression(LRP)-free survival by different statistical approaches. In a multivariate survival analysis gains on chromosomes 1q and 16q predict a reduced LRP-free survival independently from known prognostic factors. A subgroup of patients with reduced survival after radiotherapy exhibited an amplification of the chromosomal region 16q24.3. In this chromosomal region an increased copy number of FANCA, a member of the Fanconi anaemia/BRCA1 pathway could be identified. Thus, this study demonstrated that the amplification of FANCA may explain to some extent the dismal course of a subgroup of HNSCC patients after radiotherapy.

These findings may lead to improved therapy strategies since patients with poor response to radiotherapy can be identified by these genetic markers.

Please finde here slides illustrating the highlight

Contact person: Prof. Dr. Horst Zitzelsberger  , Dr. Verena Zangen

Publication

  • Bauer, V. L., Braselmann, H., Henke, M., Mattern, D., Walch, A., Unger, K., Baudis, M., Lassmann, S., Huber, R., Wienberg, J. et al. (2008) Chromosomal changes characterize head and neck cancer with poor prognosis.
    J Mol Med. 86, 1353-65

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