Prognostic value of hMLH1 methylation and microsatellite instability in pancreatic endocrine neoplasms.
BACKGROUND
The aberrant promoter methylation of the mismatch repair gene, hMLH1, is associated with microsatellite instability (MSI) in cancer cells and often is associated with a favorable prognosis.


METHODS
Pancreatic endocrine neoplasms (PENs) were obtained from 48 patients who underwent surgical resection. Methylation-specific polymerase chain reaction was used to detect methylation in the hMLH1 promoter. Tumor MSI at loci BAT26, BAT25, D2S123, D5S346, and D17S250 was determined with microsatellite polymerase chain reaction.


RESULTS
Hypermethylation of the hMLH1 promoter was present in 11 of 48 PENs (23%). Five of the 11 hMLH1-methylated PENs were found to be microsatellite unstable, and MSI was restricted to PENs with hMLH1 hypermethylation. Tumor recurrence at 2 years after surgical resection was significantly less common among the hMLH1-methylated PENs (11%), compared with the unmethylated PENs (35%; P=.038). Patients with hMLH1-methylated PENs experienced improved 5-year survival (100%) compared with patients with unmethylated tumors (56%; P=.010). Likewise, MSI-positive PENs were associated with improved survival compared with MSI-negative tumors (100% vs 59%; P=.017) at 5 years.


CONCLUSIONS
As in hereditary nonpolyposis colorectal cancer in which MSI is associated with improved survival, methylation of hMLH1 leads to MSI in PENs and affords a favorable prognosis.
House
Michael G
MG
Department of Surgery, The Johns Hopkins Medical Institutions, 600 N. Wolfe Street, Baltimore, MD 21287, USA.
Herman
James G
JG
Guo
Ming Zhou
MZ
Hooker
Craig M
CM
Schulick
Richard D
RD
Cameron
John L
JL
Hruban
Ralph H
RH
Maitra
Anirban
A
Yeo
Charles J
CJ
D048868:Adaptor Proteins, Signal Transducing; D007516:Adenoma, Islet Cell / Q000235:genetics*; D002352:Carrier Proteins; D019175:DNA Methylation; D016147:Genes, Tumor Suppressor / Q000502:physiology; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D010190:Pancreatic Neoplasms / Q000235:genetics*; D011237:Predictive Value of Tests; D011379:Prognosis
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1