Promoter CpG methylation of multiple genes in pituitary adenomas: frequent involvement of caspase-8.
The epigenetic changes in pituitary adenomas were identified by evaluating the methylation status of nine genes (RB1, p14(ARF), p16(INK4a), p73, TIMP-3, MGMT, DAPK, THBS1 and caspase-8) in a series of 35 tumours using methylation-specific PCR analysis plus sequencing. The series included non-functional adenomas (n=23), prolactinomas (n=6), prolactinoma plus thyroid-stimulating hormone adenoma (n=1), growth hormone adenomas (n=4), and adrenocorticotropic adenoma (n=1). All of the tumours had methylation of at least one of these genes and 40% of samples (14 of 35) displayed concurrent methylation of at least three genes. The frequencies of aberrant methylation were: 20% for RB1, 17% for p14(ARF), 34% for p16(INK4a), 29% for p73, 11% for TIMP-3, 23% for MGMT, 6% for DAPK, 43% for THBS1 and 54% for caspase-8. No aberrant methylation was observed in two non-malignant pituitary samples from healthy controls. Although some differences in the frequency of gene methylation between functional and non-functional adenomas were detected, these differences did not reach statistical significance. Our results suggest that promoter methylation is a frequent event in pituitary adenoma tumourigenesis, a process in which inactivation of apoptosis-related genes (DAPK, caspase-8) might play a key role.
Bello
M Josefa
MJ
Unidad de Investigación, Laboratorio Oncogenética Molecular y Epigenética del Cáncer, Hospital Universitario La Paz, Paseo Castellana 261, 28046 Madrid, Spain.
De Campos
Jose M
JM
Isla
Alberto
A
Casartelli
Cacilda
C
Rey
Juan A
JA
D000236:Adenoma / Q000235:genetics*; D000328:Adult; D000367:Age Factors; D000368:Aged; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism*; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010911:Pituitary Neoplasms / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012737:Sex Factors
C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases