Elsevier

Surgery

Volume 134, Issue 6, December 2003, Pages 902-908
Surgery

Prognostic value of hMLH1 methylation and microsatellite instability in pancreatic endocrine neoplasms

https://doi.org/10.1016/S0039-6060(03)00412-4Get rights and content

Abstract

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.

Conclusion

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.

Section snippets

Patients and tissues

Forty-eight patients who underwent resection of a PEN at The Johns Hopkins Hospital between 1991 and 2001 were studied. After permission from the Johns Hopkins University institutional review board, tissue specimens were collected retrospectively as formalin-fixed, paraffin-embedded blocks from the Department of Pathology. Information regarding tumor classification (pathologic grade, size, and stage), patient characteristics (age and gender), and clinical follow-up data was ascertained through

hMLH1 hypermethylation

Similar to our previous report that examined the importance of aberrant promoter methylation of multiple tumor suppressor genes in islet cell tumors,17 we discovered hMLH1 hypermethylation in 23% of all PENs. However, we did not find promoter methylation within the tumor-free tissue margins that were adjacent to the primary neoplasms (Fig 1). Despite careful microdissection of the tumor sections, the presence of unmethylated alleles within the hMLH1-methylated tumors likely reflects the

Discussion

Strict criteria for the determination of MSI in neoplasms that arise from the exocrine or endocrine pancreas remain unestablished. Although some studies have questioned whether microsatellite variability that is associated with less than 40% of studied markers truly reflects defective DNA mismatch repair, we classified neoplasms as MSI-positive if size variation was found for the BAT26 marker or any 2 microsatellite loci.19., 20. Overall, MSI was discovered in 5 of the 48 PENs (10%), and each

Acknowledgements

We thank Kornel Schuebel, PhD, for his expert advice about the study of MSI in human neoplasms.

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    Presented at the 24th Annual Meeting of the American Association of Endocrine Surgeons, San Diego, California, May 1l-14, 2003.

    Supported in part by grants from the Stavros S. Niarchos Foundation and National Cancer Institute grant CA-84986 of the Early Detection Research Network.

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