Loss of DAXX/ATRX expression and alternative lengthening of telomeres in insulinomas and neuroendocrine tumours of the small intestine

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URI: http://hdl.handle.net/10900/65117
Dokumentart: Dissertation
Date: 2015-09
Language: English
Faculty: 4 Medizinische Fakultät
4 Medizinische Fakultät
Department: Medizinische Fakultät
Advisor: Sipos, Bence (Prof. Dr.)
Day of Oral Examination: 2015-09-09
DDC Classifikation: 610 - Medicine and health
Keywords: Insulinom
Other Keywords: Telomer
neuroendokrine Tumoren des Dünndarms
Alternative Verlängerung der Telomere
neuroendocrine tumours of the small intestine
alternative lengthening of telomeres
License: Publishing license excluding print on demand
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Neuroendocrine tumours (NETs) are rare neoplasms with an incidence of 2- 4% per 100,000 population. Most NETs are found in the pancreas (34.2%) and the small intestine (25.8%). At time of diagnosis, 50% of all patients with NETs already have metastasis and systemic therapy is indicated. There are drugs available like somatostatin- analogues, inhibitors of the mTOR pathway and inhibitors of angiogenesis and interferon alpha. For Somatostatin- analogues a stabilisation of tumour growth is reported. The other drugs showed a prolonged survival time for months compared to placebo. However, a better understanding of the biological mechanisms of this tumour type is necessary in order to find drugs for targeted therapy. Recent studies reported that mutations in the MEN1 gene, in the DAXX/ATRX gene and in genes related to the mTOR pathway are found in pancreatic neuroendocrine tumours (PANETs). Our aim is to examine the significance of DAXX/ATRX expression and alternative lengthening of telomeres (ALT) in insulinomas, which has been investigated in PANETs, but only for a small number of insulinomas. We also address this question in NETs of the small intestine (siNETs), which has not been examined at all. We found a loss of DAXX expression in one insulinoma and a loss of ATRX expression in four insulinomas. These results correlate with ALT phenotype (p< 0.001). We revealed that a loss of DAXX/ATRX is strongly correlated with malignant behaviour (p< 0.001), a bigger tumour size(p= 0.005) and a shortened overall survival (p=0.012). In other words, finding DAXX/ATRX expression loss in insulinomas is a sign of malignancy and a poor prognosis. In siNETs, loss of DAXX/ATRX expression and ALT phenotype play a minor role in the tumourgenesis. The ALT pathway plays an important role in insulinomas and PANETs in general, therefore further studies are required to find new agents for a targeted therapy.

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