title: Prognostic and predictive roles of MGMT protein expression and promoter methylation in sporadic pancreatic neuroendocrine neoplasms.
abstract: OBJECTIVE
  O(6)-methylguanine-methyltransferase (MGMT) is an important enzyme of DNA repair. MGMT promoter methylation is detectable in a subset of pancreatic neuroendocrine neoplasms (pNEN). A subset of pNEN responds to the alkylating agent temozolomide (TMZ). We wanted to correlate MGMT promoter methylation with MGMT protein loss in pNEN, correlate the findings with clinico-pathological data and determine the role of MGMT to predict response to TMZ chemotherapy.
  
  
  METHODS
  We analysed a well-characterized collective of 141 resected pNEN with median follow-up of 83 months for MGMT protein expression and promoter methylation using methylation-specific PCR (MSP). A second collective of 10 metastasized, pretreated and progressive patients receiving TMZ was used to examine the predictive role of MGMT by determining protein expression and promoter methylation using primer extension-based quantitative PCR.
  
  
  RESULTS
  In both collectives there was no correlation between MGMT protein expression and promoter methylation. Loss of MGMT protein was associated with an adverse outcome, this prognostic value, however, was not independent from grade and stage in multivariate analysis. Promoter hypermethylation was significantly associated with response to TMZ.
  
  
  CONCLUSIONS
  Loss of MGMT protein expression is associated with adverse outcome in a surgical series of pNET. MGMT promoter methylation could be a predictive marker for TMZ chemotherapy in pNEN, but further, favourably prospective studies will be needed to confirm this result and before this observation can influence clinical routine.
authors.affiliation: Department of Pathology, Institute of Clinical Pathology, University of Bern, Bern, Switzerland.
authors.forename: Anja Maria
authors.initials: AM
authors.lastname: Schmitt
authors.forename: Marianne
authors.initials: M
authors.lastname: Pavel
authors.forename: Thomas
authors.initials: T
authors.lastname: Rudolph
authors.forename: Heather
authors.initials: H
authors.lastname: Dawson
authors.forename: Annika
authors.initials: A
authors.lastname: Blank
authors.forename: Paul
authors.initials: P
authors.lastname: Komminoth
authors.forename: Erik
authors.initials: E
authors.lastname: Vassella
authors.forename: Aurel
authors.initials: A
authors.lastname: Perren
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics* / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D010190:Pancreatic Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D011379:Prognosis; D011401:Promoter Regions, Genetic; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C513496:MIB1 ligase, human; D044767:Ubiquitin-Protein Ligases; D045643:DNA Repair Enzymes; D000077204:Temozolomide