Expression of O6-Methylguanine DNA Methyltransferase (MGMT) in Midgut and Pancreatic Neuroendocrine Tumors, Solid Pseudopapillary Tumors and Acinar Cell Carcinomas
Markus D Siegelin, Sofia Shaikh, Robert Fine, Helen Remotti. Columbia University College of Physicians & Surgeons, New York, NY
Background: MGMT is a DNA repair enzyme that demethylates DNA to prevent physiologically induced intrinsic apoptotic cell death initiated by the DNA-damage response pathway. Accordingly, silenced expression of MGMT has been shown to be detrimental to the response rate of many tumor entities to the oral alkylating agent, temozolomide (TMZ), including neuroendocrine tumors. To predict response rate of pancreatic and midgut neuroendocrine tumors (NET-P and NET-M), solid pseudopapillary tumors of the pancreas (SP) and acinar cell carcinoma of the pancreas (AC) to alkylating reagents, we analysed the expression of MGMT in these entities.
Design: NET-P, NET-M, SP and AC were located through review of the pathology records at Columbia University Medical Center. Tissue microarrays (TMAs) comprising 96 tumor samples, consisting of NET-P (n=54), NET-M (n=29), SP (n=10) and AC (n=2), were created. Each tumor was represented by three cores on the array to ensure representative expression analysis. TMAs were subjected to immunohistochemistry (IHC) by the application of a monoclonal antibody against MGMT (clone: MT3.1, dilution: 1:2000). Nuclear expression of MGMT was independently determined by two pathologists by virtue of a prospective evaluation. Nuclear MGMT expression was either scored as positive or negative.
Results: TMAs were analyzed for nuclear MGMT expression by IHC. IHC for MGMT in our subset of tumors produced a reliable, robust expression pattern. Out of 54 NET-P 26 tumors did not express MGMT (48.1%) in the presence of nuclear MGMT positivity in pancreatic ducts and acini (internal positive control). Similarly, among 29 NET-M 17 tumors were deficient for MGMT (58.6%). All SP and AC revealed nuclear expression of MGMT, none of these tumors were MGMT-deficient. Significant heterogenous expression of MGMT, particularly in NET-M, was detected and these tumors were classified as positive for MGMT expression.
Conclusions: In our study, both NET-P and NET-M reveal in almost 50% of our cases loss of MGMT expression. These results suggest that NET-P and NET-M, but not SP and AC might be equally responsive to treatment with alkylating reagents. Therefore, pathological analysis of MGMT expression in NET-P and NET-M is warranted in order to determine patients with better prognosis and to identify the subpopulation of patients that most likely will benefit from TMZ treatment.
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 248, Wednesday Morning