MGMT expression and pituitary tumours: relationship to tumour biology.
Over the past half decade, temozolomide, an oral akylating chemotherapeutic agent, has been shown to have significant activity in the management of aggressive pituitary tumours. The expression of 06-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, is an important predictor of response to therapy. Low MGMT expression has been reported with a higher frequency amongst more aggressive pituitary tumours, suggesting MGMT may play a role in pituitary tumour progression. In this study, we performed a microarray analysis to determine whether there was a distinct gene expression profile between tumours with low MGMT and high MGMT expression. Overall, 1,403 differentially expressed genes were identified with raw p values less than 0.05. Gene set enrichment analysis (GSEA) revealed significant differences in the gene expression profile between high and low MGMT expressing pituitary tumours. High MGMT expressing pituitary tumours were found to have upregulation of components of the FGFR family and downstream signaling cascades such as PI3 K/Akt and MAPK pathways. Activation of genes involved in the DNA damage response and DNA repair pathways, as well as genes involved in transcription, were identified in pituitary tumours with low MGMT expression. These results form the basis of our proposed model to describe the role of MGMT in pituitary tumorigenesis.
Cancer Genetics Unit, Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, NSW, Australia. a.mccormack@garvan.org.au
Ann
A
McCormack
Warren
W
Kaplan
Anthony J
AJ
Gill
Nicholas
N
Little
Raymond
R
Cook
Bruce
B
Robinson
Roderick
R
Clifton-Bligh
D000328:Adult; D000368:Aged; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010911:Pituitary Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide