ERC Short Title 10 NET: Cracking the epigenetic code 11

Abstract 20 The field of epigenetics has evolved rapidly over recent years providing insight into the 21 tumorigenesis of many solid and haematological malignancies. Determination of epigenetic 22 modifications in neuroendocrine tumour (NET) development is imperative if we are to improve our 23 understanding of the biology of this heterogenous group of tumours. Epigenetic marks such as 24 methylation of RASSF1A are frequent findings in NETs of all origins and may be associated with 25 worse prognosis. Micro RNA signatures and histone modifications have been identified which 26 differentiate subtypes of NET and distinguish NET from adenocarcinoma in cases of diagnostic 27 uncertainty. 28 Historically candidate gene driven approaches have yielded limited insight to the epigenetics of NET. 29 Recent progress has been facilitated by development of high throughput tools including second 30 generation sequencing and arrays for analysis of the ‘epigenome ’ of tumour and normal tissue, 31 permitting unbiased approaches such as exome sequencing which identified mutations of chromatin 32 remodelling genes ATRX/DAXX in 44 % of pancreatic NETs. 33 Epigenetic changes are reversible and therefore represent an attractive therapeutic target, to date 3