We are delighted to award the 2020 NCUK grant to Dr Marc Ooft, Consultant Histopathologist, Kings College Hospital.
His research alongside the NET GeCIP group is focusing on ‘Improving patient stratification through epigenetic and tumour microenvironment analysis of the 100,000 Genomes project neuroendocrine tumour cohort.’
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. The NET (neuroendocrine tumour) 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 mutations which can be actioned upon potential therapy.
However, epigenetic alterations (which are alterations outside of the genome) are significantly more common than mutations in NETs with DNA methylation found in >70% of NETs in different subsites. We therefore set out in this proposal to augment the 100K WGS data by performing epigenetic and tumour microenvironment (alteration in the environment of the tumour itself) analyses in order to improve patient stratification and potentially identify novel therapeutic approaches.
No previous studies 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 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 standardized genetic and epigenetic markers for NETs to aid prognostication and optimize stratification of patients being considered for novel immunotherapy and other targeted therapies.