Project Leader: Dr Chrissie Thirlwell
Neuroendocrine Tumors (NETs) are a heterogeneous group of neoplasms which arise from the hormone-producing cells of the bodyís nervous and endocrine systems. NETs affect 1/50 000 of the UK population. The project aims to carry out an integrated (epi)genomic analysis of the NET BioBank established at the Royal Free and UCL Hospitals to identify new biomarkers for translation into diagnostics and therapeutics
The Neuroendocrine Tumour (NET) Unit at the Royal Free Campus of UCL Hospitals has an international reputation for the management of neuroendocrine tumour patients. It currently receives around 10 new referrals per month and has an active patient cohort of over 800 patients. We receive referrals from across the UK as well as from abroad. It is the designated centre for NETs within the North London Cancer Network.
Due to the rarity of NETs and difficulty in obtaining fresh tissue and archival samples, very little is known about the (epi)genetic and germline mutations associated with neuroendocrine tumours ñ which encompass a clinically and genetically heterogeneous group. To date, studies have been small and under-powered. Clinical trials have included small patient numbers and are often non-randomised phase II trials comparing a new therapy against a non-standardised first line treatment.
In order to improve both treatment and outcome in NETs, better understanding of their biology and the biological pathways involved is imperative (reviewed in (Modlin et al., 2008)). Currently, the use of targeted treatments is limited and management challenging due to the lack of knowledge of the molecular pathogenesis and mechanistic regulation of these tumours (Barakat et al., 2004).
The tissue bank will potentially be available for national and international collaboration with the aim of improving the quality and quantity of research into NETs in both the clinical and basic science settings.
(Epi)genomic analysis of neuroendocrine tumours
Changes in methlyation pattern across the genome are known to cause tumourigenesis. Hypermethylation of gene promoter regions and genome-wide hypomethylation have both been associated with cancer (reviewed in (Feinberg et al)). Cellular proliferation and tumourigenesis is promoted through aberrant promoter hypermethylation of tumour suppressor genes resulting in loss of function. Global hypomethylation is observed in a variety of tumour types including breast, colorectal, oral and lung cancers. Hypomethylation is thought to contribute to tumourigenesis through activation of oncogenes and the promotion of genomic instability.
Initially we will undertake genome-wide methylation analysis on our entire cohort of neuroendocrine tumours in order to determine the methylation profiles of differing NET types. This will improve diagnostic accuracy and potentially identify new therapeutic targets and biomarkers. These studies will be performed on high-throughput analysis platforms based on micoarrays and next-generation sequencing. In parallel, we will analyse the mRNA expression profiles of these tumours to enable integrated (epi)genomic analysis of these intriguing tumours.
1. Barakat, M.T., Meeran, K. & Bloom, S.R. (2004). Neuroendocrine tumours. Endocr Relat Cancer, 11, 1-18.
2. Feinberg, A.P, Tycko B. The history of cancer epigenetics. (2004) Nat. Rev. Cancer, 4, 143-53.
3. Modlin, I.M., Oberg, K., Chung, D.C., Jensen, R.T., de Herder, W.W., Thakker, R.V., Caplin, M., Delle Fave, G., Kaltsas, G.A., Krenning, E.P., Moss, S.F., Nilsson, O., Rindi, G., Salazar, R., Ruszniewski, P. & Sundin, A. (2008). Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol, 9, 61-72.
Dr Anna Karpathakis - Clinical Research Fellow
Prof. Daniel Hochhauser - UCL Cancer Institute
Dr Martyn Caplin - Royal Free Hospital
Prof. Brian Davidson - Royal Free Hospital
Prof. Marc Winslett - Royal Free Hospital
Dr Tim Meyer - Royal Free Hospital and UCL Cancer Institute
Mr Tom Kurzawinksi - UCL Hospitals
Dr Steve Periera - UCL Hospitals