MGMT (O6-MethylguanineDNA Methyltransferase) Is Inactivated in a Significant Subset of Distal Esophageal Adenocarcinomas: Implications for Neoadjuvant Chemoradiation Therapy.
Mikhail Lisovsky, Mari Mino-Kenudson, Joel Lefferts, Elizabeth Courville, Bassem Zaki, Laura N Calvo, Ted S Hong, Gregory J Tsongalis, Gregory Y Lauwers, Amitabh Srivastava. Dartmouth Hitchcock Medical Center, Lebanon, NH; Massachusetts General Hospital, Boston
Background: Epigenetic silencing of DNA-repair gene MGMT by promoter methylation compromises DNA repair and sensitizes tumors to alkylating chemotherapeutic agents. Temozolomide is an alkylating agent shown to be effective in MGMT-methylated pancreatic endocrine tumors and glioblastomas. Loss of MGMT expression is a surrogate marker of MGMT promoter methylation. The goal of this study was to ascertain the prevalence of MGMT loss in distal esophageal adenocarcinoma (EA) using immunohistochemistry, and to determine whether the immunohistochemical findings correlate with MGMT promoter methylation status.
Design: The study group consisted of 62 patients (mean age 62.4 yrs, M:F = 53:9), all of whom were treated with neoadjuvant platinum-based chemoradiation regimen followed by esophagectomy. MGMT expression was evaluated immunohistochemically in the pretreatment biopsies using monoclonal anti-MGMT antibody (Novus Biologicals). Nuclear staining was graded semi-quantitatively for extent (focal <25%; diffuse >25%) and intensity (weak, moderate, strong). Cases were then scored as 0 (negative), 1 (focal weak), 2 (focal moderate-strong), 3 (diffuse but weak-moderate), and 4 (diffuse strong). MGMT promoter methylation was analyzed using nested methylation-specific PCR. Immunohistochemical findings were correlated with MGMT promoter methylation status and with post-treatment T and N stage in esophagectomy specimens.
Results: Immunohistochemistry performed on pre-treatment biopsies showed complete (score 0) or near complete (score 1) loss of MGMT staining in 14 and 3 cases, respectively (17/62; 27%). Score 2 was present in 3 (5%) cases, score 3 in 12 (19%) cases, and score 4 in 30 (49%) cases. DNA from 8/17 biopsies with loss of MGMT staining was subjected to methylation specific PCR and all 8 (100%) showed promoter methylation. In contrast, 4 of 6 (67%) cases with strong MGMT expression (score 4) showed no methylation, while 2 of 6 (33%) were methylated (p=0.015). Loss of MGMT staining did not correlate with post-treatment ypT and ypN stage in esophagectomy specimens.
Conclusions: A significant subset (27%) of distal esophageal adenocarcinomas shows complete or near complete loss of MGMT protein expression, which correlates with promoter methylation. Immunohistochemical assessment of MGMT may be helpful in selecting patients for future trials to assess the value of alkylating agents in neoadjuvant therapy of EA.
Monday, February 28, 2011 1:00 PM
Poster Session II # 93, Monday Afternoon