TY - JOUR
T1 - A comprehensive characterisation of phaeochromocytoma and paraganglioma tumours through histone protein profiling, DNA methylation and transcriptomic analysis genome wide
AU - Chatzikyriakou, Prodromos
AU - Brempou, Dimitria
AU - Quinn, Mark
AU - Fishbein, Lauren
AU - Noberini, Roberta
AU - Anastopoulos, Ioannis N.
AU - Tufton, Nicola
AU - Lim, Eugenie S.
AU - Obholzer, Rupert
AU - Hubbard, Johnathan G.
AU - Moonim, Mufaddal
AU - Bonaldi, Tiziana
AU - Nathanson, Katherine L.
AU - Izatt, Louise
AU - Oakey, Rebecca J.
N1 - Funding Information:
The research was supported by a research project grant from the Bernice Bibby Research Trust (to LI, PC and RJO) and R21 CA185953 from the National Institutes of Health, National Cancer Institute (to KLN). The research was supported by the Wellcome Trust through the Research Equipment Grant 212917/Z/18/Z (to RJO); by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy’s and St. Thomas’ NHSFT by a project grant (to LI, PC and RJO). The National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at Guy’s and St. Thomas’ NHSFT, in partnership with King’s College London funded the PhD scholarship to PC. DB is in receipt of a PhD scholarship funded jointly by GSK and the NIHR Biomedical Research Centre at Guy’s and St. Thomas’ NHSFT through DRIVE-Health. MQ is in receipt of a fellowship funded by the National Institute for Health Research (NIHR). TB’s research activity is supported by grants from the Italian Association for Cancer Research (grant# IG-2018-21834). Mass spec proteomics analyses were carried out with funding from the EPIC-XS, project number 823839, funded by the Horizon 2020 programme of the European Union. NT was supported by The Medical College of St. Bartholomew’s Hospital Trust. ESL was supported by Barts Charity (MGU0468) and the Medical Research Council UKRI (MR/W001101/1).
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - BackgroundPhaeochromocytomas 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.ResultsOut 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.ConclusionsCombined 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.
AB - BackgroundPhaeochromocytomas 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.ResultsOut 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.ConclusionsCombined 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.
KW - Cancer predisposition
KW - DNA methylation
KW - Epigenetics
KW - Germline pathogenic variant
KW - Histone post-translational modifications
KW - Mass spectrometry
KW - Paraganglioma
KW - Phaeochromocytoma
KW - SDH
KW - Succinate dehydrogenase
UR - http://www.scopus.com/inward/record.url?scp=85180228122&partnerID=8YFLogxK
U2 - 10.1186/s13148-023-01598-3
DO - 10.1186/s13148-023-01598-3
M3 - Article
AN - SCOPUS:85180228122
SN - 1868-7075
VL - 15
JO - Clinical Epigenetics
JF - Clinical Epigenetics
IS - 1
M1 - 196
ER -
