A comprehensive characterisation of phaeochromocytoma and paraganglioma tumours through histone protein profiling, DNA methylation and transcriptomic analysis genome wide

Prodromos Chatzikyriakou; Dimitria Brempou; Mark Quinn; Lauren Fishbein; Roberta Noberini; Ioannis N Anastopoulos; Nicola Tufton; Eugenie S Lim; Rupert Obholzer; Johnathan G Hubbard; Mufaddal Moonim; Tiziana Bonaldi; Katherine L Nathanson; Louise Izatt; Rebecca J Oakey

doi:10.1186/s13148-023-01598-3

A comprehensive characterisation of phaeochromocytoma and paraganglioma tumours through histone protein profiling, DNA methylation and transcriptomic analysis genome wide

Clin Epigenetics. 2023 Dec 20;15(1):196. doi: 10.1186/s13148-023-01598-3.

Authors

Prodromos Chatzikyriakou^{1

2}, Dimitria Brempou¹, Mark Quinn¹, Lauren Fishbein^{3

4

5

6}, Roberta Noberini⁷, Ioannis N Anastopoulos⁸, Nicola Tufton⁹, Eugenie S Lim⁹, Rupert Obholzer¹⁰, Johnathan G Hubbard¹¹, Mufaddal Moonim^{12

13}, Tiziana Bonaldi^{7

14}, Katherine L Nathanson^{3

4}, Louise Izatt¹⁵, Rebecca J Oakey¹⁶

Affiliations

¹ Department of Medical and Molecular Genetics, King's College London, London, SE1 9RT, UK.
² Comprehensive Cancer Centre, King's College London, London, SE5 8AF, UK.
³ Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Abramson Cancer Center, Perelman School of Medicine, Philadelphia, PA, USA.
⁵ Division of Endocrinology, Diabetes and Metabolism in the Department of Medicine Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁶ Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
⁷ Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Via Adamello 16, 20139, Milan, Italy.
⁸ Department of Biomolecular Engineering, UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA, 95064, USA.
⁹ Department of Endocrinology, St. Bartholomew's Hospital, Barts Health NHS Trust, and William Harvey Research Institute, Queen Mary University of London, London, UK.
¹⁰ Department of ENT and Skull Base Surgery, Guy's and St Thomas' NHS Foundation Trust, London, SE1 9RT, UK.
¹¹ Department of Endocrine Surgery, Guy's and St Thomas' NHS Foundation Trust, London, SE1 9RT, UK.
¹² Department of Cellular Pathology, Guy's and St Thomas' NHS Foundation Trust, London, SE1 9RT, UK.
¹³ Imperial College Healthcare NHS Trust, London, UK.
¹⁴ Department of Oncology and Hematology-Oncology, University of Milano, Via Festa del Perdono 7, 20122, Milan, Italy.
¹⁵ Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, SE1 9RT, UK.
¹⁶ Department of Medical and Molecular Genetics, King's College London, London, SE1 9RT, UK. rebecca.oakey@kcl.ac.uk.

Abstract

Background: Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours. Pathogenic variants have been identified in more than 15 susceptibility genes; associated tumours are grouped into three Clusters, reinforced by their transcriptional profiles. Cluster 1A PPGLs have pathogenic variants affecting enzymes of the tricarboxylic acid cycle, including succinate dehydrogenase. Within inherited PPGLs, these are the most common. PPGL tumours are known to undergo epigenetic reprograming, and here, we report on global histone post-translational modifications and DNA methylation levels, alongside clinical phenotypes.

Results: Out of the 25 histone post-translational modifications examined, Cluster 1A PPGLs were distinguished from other tumours by a decrease in hyper-acetylated peptides and an increase in H3K4me2. DNA methylation was compared between tumours from individuals who developed metastatic disease versus those that did not. The majority of differentially methylated sites identified tended to be completely methylated or unmethylated in non-metastatic tumours, with low inter-sample variance. Metastatic tumours by contrast consistently had an intermediate DNA methylation state, including the ephrin receptor EPHA4 and its ligand EFNA3. Gene expression analyses performed to identify genes involved in metastatic tumour behaviour pin-pointed a number of genes previously described as mis-regulated in Cluster 1A tumours, as well as highlighting the tumour suppressor RGS22 and the pituitary tumour-transforming gene PTTG1.

Conclusions: Combined transcriptomic and DNA methylation analyses revealed aberrant pathways, including ones that could be implicated in metastatic phenotypes and, for the first time, we report a decrease in hyper-acetylated histone marks in Cluster 1 PPGLs.

Keywords: Cancer predisposition; DNA methylation; Epigenetics; Germline pathogenic variant; Histone post-translational modifications; Mass spectrometry; Paraganglioma; Phaeochromocytoma; SDH; Succinate dehydrogenase.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adrenal Gland Neoplasms* / genetics
Adrenal Gland Neoplasms* / metabolism
Adrenal Gland Neoplasms* / pathology
DNA Methylation
Gene Expression Profiling
Histones / genetics
Histones / metabolism
Humans
Paraganglioma* / genetics
Paraganglioma* / pathology
Pheochromocytoma* / genetics
Pheochromocytoma* / metabolism
Pheochromocytoma* / pathology

Substances

Histones

Abstract

Publication types

MeSH terms

Substances

Grants and funding