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Improving patient stratification through epigenetic and tumour microenvironment analysis of the 100,000 Genomes project Neuroendocrine tumour cohort (NET GeCIP).

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Lay summary

The 100,000 (100K) Genomes Project was delivered as a transformation project across the NHS and was the largest undertaking of whole genome sequencing (WGS) globally in routine clinical care (https://www.genomicsengland.co.uk/about-genomics-england/the-100000- genomes-project/). WGS is powerful in that it can identify many genomic aberrations (single nucleotide variants, deletions, insertions, structural variants along with pathogenic viral insertions). The NET GeCIP was formed to analyse and interpret WGS data produced from 130 NET cases recruited through the 100K project. Analysis of the cancer arm of 100K genomes legacy data has identified that whole genome sequencing identified a potential therapeutic target or clinical trial in 50% of cancer cases. We know that NETs have a very low background mutation rate and few actionable mutations which can guide therapeutic decision making. However, epigenetic alterations are significantly more common than mutations in NETs with DNA methylation found in >70% of NETs in different subsites (Stalberg 2016, Cives 2016). We therefore set out in this proposal to augment the 100K WGS data by performing epigenetic and tumour microenvironment analyses in order to improve patient stratification and potentially identify novel therapeutic approaches. The Thirlwell group has previously identified molecular subgroups of pancreatic and intestinal NETs based on integrated DNA methylation and transcriptome analyses (Pipinikas 2015, Karpathakis 2016, Karpathakis 2017). However, there are no studies which have integrated genome-wide methylation patterns of neuroendocrine tumours with WGS. Furthermore, few studies have also looked at the influence of the tumour micro-environment on the methylation profiles of NETs. The latter is important as the heterogeneous (epi)genetic profiles in NETs at different primary sites might be microenvironment driven and this could also possibly correlate with biological aggressiveness of these tumours. Through the work outlined in this project genetic and epigenetic correlations with histopathological predictors of malignant behaviour will be determined. Elucidating the gaps and inconsistencies in our (epi)genetic knowledge of NETs will help to improve patient stratification and prognostication. The 100K project provided infrastructure and funds to recruit 17,000 cancer patients and undertake WGS. No funds are available for other genomic analyses of these cases. However, DNA has been extracted and stored which will be utilised for the DNA methylation analysis outlined in this proposal. Within the NET GeCIP there is expertise in WGS and the infrastructure to define the immune landscape in NETs through histopathological and DNA methylation analyses (MethylCybersort). The overall aim of this project is to further our understanding of the genetic and epigenetic changes in conjunction with detailed histopathological assessment and clinical annotation. This will lead to future work culminating in the development of standardised genetic and epigenetic markers for NETs to aid prognostication and optimize stratification of patients being considered for novel immunotherapy and other targeted therapies.

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