Global DNA Methylation Analysis Identifies Two Discrete clusters of Pheochromocytoma with Distinct Genomic and Genetic Alterations.
Pheochromocytomas and paragangliomas (PPGLs) are rare and frequently heritable neural-crest derived tumours arising from the adrenal medulla or extra-adrenal chromaffin cells respectively. The majority of PPGL tumours are benign and do not recur with distant metastases. However, a sizeable fraction of these tumours secrete vasoactive catecholamines into the circulation causing a variety of symptoms including hypertension, palpitations and diaphoresis. The genetic landscape of PPGL has been well characterized and more than a dozen genes have been described as recurrently mutated. Recent studies of DNA-methylation have revealed distinct clusters of PPGL that share DNA methylation patterns and driver mutations, as well as identified potential biomarkers for malignancy. However, these findings have not been adequately validated in independent cohorts. In this study we use an array-based genome-wide approach to study the methylome of 39 PPGL and 4 normal adrenal medullae. We identified two distinct clusters of tumours characterized by different methylation patterns and different driver mutations. Moreover, we identify genes that are differentially methylated between tumour subcategories, and between tumours and normal tissue.
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Samuel
S
Backman
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Rajani
R
Maharjan
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Alberto
A
Falk-Delgado
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Joakim
J
Crona
Department of Surgery, Marien-Hospital, Euskirchen, Germany.
Kenko
K
Cupisti
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Peter
P
Stålberg
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Per
P
Hellman
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Peyman
P
Björklund
D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D006801:Humans; D008297:Male; D008875:Middle Aged; D010673:Pheochromocytoma / Q000235:genetics* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D055815:Young Adult
D017382:Reactive Oxygen Species