DNA Strategic Epigenetic Biomarkers in Melanoma

Background:

Immune checkpoint inhibitors (ICi) have changed the therapeutic landscape for many malignancies including melanoma. Stratifying patients for adjuvant or early treatment with these agents is crucial to avoid significant toxicities and unnecessary NHS health costs. Detecting high-risk patients likely to benefit is therefore a clinical priority whilst validating cancer-specific methylation will increase our understanding of the mechanisms driving metastasis in melanoma. Previous work by this group has found gene-specific DNA methylation to be associated with melanoma metastasis1. Development of a robust assay for NHS delivery is achievable, but requires further discovery and optimisation.

Proposal:

To use a multiplexed MALDI-TOF mass spectrometry system for detection of methylated DNA sequences in a 384-well format allowing simultaneous testing for cancer-associated methylation at multiple CpG islands in multiple genes in multiple samples. To test this system on serial blood samples already collected from 287 melanoma patients in NHS Tayside and subsequently to validate the assay in a large independent cohort from the AVAST-M clinical trial (collaboration Professor Mark Middleton, Oxford). To initially test 3 genes (TFPI2, P4HA3, AGTR1) shown in pilot studies to be strong candidates as epigenetic biomarkers for metastatic melanoma. To add up to 3 further epigenetic candidates from discovery work developed as a core part of this project. Overall aim is to develop a methylation biomarker panel as a strategic assay for use in an NHS diagnostic setting.