Telomere maintenance mechanism (TMM)

Reactivation and expression of telomerase is an important hallmark for around 85% of all tumors to maintain telomeres and gain immortality. ALT is less commonly used, but has shown high prevalence in sarcoma and astrocytoma.
In cooperation with clinical partners we focused on the role of TMM in human glioblastoma multiform (GBM), an aggressive form of astrocytoma brain tumors. Our data support the known high prevalence of ALT in low-grade astrocytoma and in GBM subclasses with a better clinical outcome. TMM were evaluated by measuring telomerase activity (TA) and by detection of long telomeres typically seen with ALT. TA positive cells regulate telomere lengths around a mean of 5-10 kb, whereas in ALT cells the telomeres are very large up to 20 kb with considerable heterogeneity in length. We established a PCR based method to measure both mean telomere lengths and expressed telomeres. Non-coding telomeric repeat–containing RNA (TERRA or TelRNA) transcripts have been recently identified and reported as key component of telomeres with inhibitory function on telomerase. We could demonstrate in astrocytoma that TERRA expression clearly correlates with tumor grade and TMM (Sampl et al 2012). TERRA expression showed correlation to outcome of this patient series and indicate that TERRA may be prognostic in astrocytoma.

Figure. Potentially prognostic relations between telomere expression (TERRA) and maintenance mechanisms TA and ALT in a GBM cohort identified (Sampl et al 2012).

Students: SibyllePramhas, Sandra Sampl
Collaborations:
Matthias Preusser, Christine Marosi, Johannes Hainfellner (Medical University of Vienna)

In cooperation with epidemiological partners we started to analyze polymorphism in telomerase genes.
Blood cells were analyzed from close to 4000 participants with a risk of colorectal polyps and colorectal cancer (CRC) as part of the ongoing colorectal cancer study of Austria (CORSA). We focused on a polymorphic tandem repeats minisatellite, termed MNS16A, located downstream of the hTERT gene and known to influence hTERT expression. We identified five different variable number of tandem repeats by PCR and sequencing, including one newly discovered rare variant. The variant 274 allele was associated with a 2.7-fold increased risk of CRC compared with the variant 302 wild-type (OR=2.69; 95% CI=1.11-6.50; P=0.028) indicating that telomerase associated polymorphisms can be confirmed as biomarkers for assessment of CRC risk by further studies (Hofer et al. 2011).

Students: Monika Hunjadi, Sandra Sampl
Collaborations: Andrea Gsur (Institute of Cancer Research)

In cooperation with clinical partners we study telomere maintenance mechanisms in colorectal cancer
Students: Sandra Sampl, Juliane Hadolt, Philip Kienzl
Collaborations:
Stefan Stättner (KFJ Hospital/Social Medical Center South, Vienna)
Brigitte Marian (Institute of Cancer Research)
Roger R. Reddel (Childrens’s Medical Research Institute, Sydney, NSW, Australia)

In cooperation with partners from Veterinary Universities (Vienna and Raleigh NC, USA) we study telomere maintenance mechanisms in soft tissue sarcoma.
Student: Theresa Kreilmeier
Collaborations:
Marlene Hauck (NC State College of Veterinary Medicine, USA)
Miriam Kleiter (University of Veterinary Medicine, Vienna)