Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumours characterised by substantial clinical variability and a complex genetic basis. Although major advances have been made in identifying inherited and somatic driver mutations, including alterations in NF1, VHL, RET, HRAS, and ATRX, a significant subset of PPGL cases still lack identifiable drivers, creating a persistent “driver deficit.” Understanding these unresolved genetic events is essential for improving diagnosis, risk stratification, and treatment, particularly for patients with metastatic disease.
Previous work conducted by our group has included short-read whole-genome sequencing (WGS) of PPGL and genome-wide DNA methylation profiling using Illumina EPIC arrays. Although these analyses identified several candidate structural variants and epigenetic alterations, many rearrangements could not be resolved due to the limitations of short-read sequencing, especially in repetitive or complex genomic regions.
This project will employ Oxford Nanopore long-read sequencing (LRS) on selected PPGL samples to overcome these limitations. Nanopore sequencing offers the ability to generate long contiguous reads, enabling accurate detection of intragenic variants, structural rearrangements, fusion events, and tumour-specific methylation signatures in a single assay.
The project aims to:
1. Identify previously undetectable PPGL driver mutations and structural variants.
2. Resolve complex rearrangements such as the previously observed but inconclusive fusion event.
3. Compare methylation patterns derived from LRS with existing EPIC array profiles to validate emerging long-read methylation methods.
4. Provide a robust dataset to support high-impact publications and future multimillion-pound funding applications focused on rare tumour genomics.
This project will significantly advance understanding of PPGL molecular pathogenesis and has strong translational potential for improving diagnostics and clinical management.
