title: O6-Methylguanine-DNA methyltransferase status in neuroendocrine tumours: prognostic relevance and association with response to alkylating agents.
abstract: BACKGROUND
  O(6)-Methylguanine-DNA methyltransferase (MGMT) loss of expression has been suggested to be predictive of response to temozolomide in neuroendocrine tumours (NETs), but so far, only limited data are available. We evaluated the prognostic and predictive value of MGMT status, assessed by two molecular methods and immunohistochemistry, in a large series of NETs of different origins.
  
  
  METHODS
  A total of 107 patients, including 53 treated by alkylants (temozolomide, dacarbazine or streptozotocin), were retrospectively studied. In each case, we used methyl-specific PCR (MS-PCR) and pyrosequencing for evaluation of promoter methylation and immunohistochemistry for evaluation of protein status.
  
  
  RESULTS
  MGMT promoter methylation was detected in 12 out of 99 (12%) interpretable cases by MS-PCR and in 24 out of 99 (24%) by pyrosequencing. O(6)-Methylguanine-DNA methyltransferase loss of expression was observed in 29 out of 89 (33%) interpretable cases. Status of MGMT was not correlated with overall survival (OS) from diagnosis. Progression-free survival and OS from first alkylant use (temozolomide, dacarbazine and streptozotocin) were higher in patients with MGMT protein loss (respectively, 20.2 vs 7.6 months, P<0.001 and 105 vs 34 months, P=0.006) or MGMT promoter methylation assessed by pyrosequencing (respectively, 26.4 vs 10.8 months, P=0.002 and 77 vs 43 months, P=0.026).
  
  
  CONCLUSIONS
  Our results suggest that MGMT status is associated with response to alkylant-based chemotherapy in NETs.
authors.affiliation: 1] Hospices Civils de Lyon, Hôpital Edouard Herriot, Service d'oncologie Digestive, 69437 Lyon, France [2] INSERM, UMR 1052, Lyon Cancer Research Center, Faculté Laennec, 69372 Lyon, France [3] Université de Lyon, Université Claude Bernard Lyon 1, 69622 Villeurbanne, France.
authors.forename: T
authors.initials: T
authors.lastname: Walter
authors.affiliation: Hospices Civils de Lyon, Hôpital Edouard Herriot, Service d'oncologie Digestive, 69437 Lyon, France.
authors.forename: B
authors.initials: B
authors.lastname: van Brakel
authors.affiliation: INSERM, UMR 1052, Lyon Cancer Research Center, Faculté Laennec, 69372 Lyon, France.
authors.forename: C
authors.initials: C
authors.lastname: Vercherat
authors.affiliation: 1] INSERM, UMR 1052, Lyon Cancer Research Center, Faculté Laennec, 69372 Lyon, France [2] Université de Lyon, Université Claude Bernard Lyon 1, 69622 Villeurbanne, France [3] Hospices Civils de Lyon, Hôpital Edouard Herriot, Service Central d'Anatomie et Cytologie Pathologiques, 69437 Lyon, France.
authors.forename: V
authors.initials: V
authors.lastname: Hervieu
authors.affiliation: Hospices Civils de Lyon, Hôpital Edouard Herriot, Service d'oncologie Digestive, 69437 Lyon, France.
authors.forename: J
authors.initials: J
authors.lastname: Forestier
authors.affiliation: 1] INSERM, UMR 1052, Lyon Cancer Research Center, Faculté Laennec, 69372 Lyon, France [2] Université de Lyon, Université Claude Bernard Lyon 1, 69622 Villeurbanne, France [3] Hospices Civils de Lyon, Hôpital Edouard Herriot, Hépatogastroentérologie, 69437 Lyon, France.
authors.forename: J-A
authors.initials: JA
authors.lastname: Chayvialle
authors.affiliation: Hospices Civils de Lyon, Hôpital Edouard Herriot, Service d'oncologie Digestive, 69437 Lyon, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Molin
authors.affiliation: Hospices Civils de Lyon, Hôpital Edouard Herriot, Service d'oncologie Digestive, 69437 Lyon, France.
authors.forename: C
authors.initials: C
authors.lastname: Lombard-Bohas
authors.affiliation: 1] INSERM, UMR 1052, Lyon Cancer Research Center, Faculté Laennec, 69372 Lyon, France [2] Université de Lyon, Université Claude Bernard Lyon 1, 69622 Villeurbanne, France [3] Hospices Civils de Lyon, Hôpital Edouard Herriot, Service Central d'Anatomie et Cytologie Pathologiques, 69437 Lyon, France.
authors.forename: M-O
authors.initials: MO
authors.lastname: Joly
authors.affiliation: 1] INSERM, UMR 1052, Lyon Cancer Research Center, Faculté Laennec, 69372 Lyon, France [2] Université de Lyon, Université Claude Bernard Lyon 1, 69622 Villeurbanne, France [3] Hospices Civils de Lyon, Hôpital Edouard Herriot, Service Central d'Anatomie et Cytologie Pathologiques, 69437 Lyon, France.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Scoazec
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D019175:DNA Methylation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007078:Ileal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D008297:Male; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D019853:O(6)-Methylguanine-DNA Methyltransferase