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Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
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Microsatellite instability in gallbladder carcinoma
Andrea P Moy1, Mohammad Shahid, Cristina R Ferrone
1Pathology Service, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Warren 256, Boston, MA, 02114, USA.
Virchows Archiv : an International Journal of Pathology
|February 15, 2015
Summary
Microsatellite instability (MSI) is rare in gallbladder cancer. Hypermethylation of LINE-1 DNA, a marker of global methylation, correlates with mismatch repair deficiency, suggesting a unique tumor subtype and potential therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Genetic abnormalities in gallbladder carcinoma (GBC) pathogenesis are not fully understood.
- The role of mismatch repair (MMR) and microsatellite instability (MSI) in GBC is largely unexplored.
- Global DNA methylation, assessed by LINE-1, has not been studied in GBC.
Purpose of the Study:
- To investigate the frequency and significance of MSI and MMR protein expression in GBC.
- To evaluate the methylation status of LINE-1 in GBC.
- To explore potential therapeutic implications of these molecular alterations.
Main Methods:
- Immunohistochemistry for MMR proteins (MSH2, MSH6, MLH1, PMS2) in 77 GBCs.
- LINE-1 mRNA in situ hybridization to assess global DNA methylation.
- Fluorescence in situ hybridization for HER2 amplification.
- Multiplex PCR for genotyping 24 cancer-related genes.
Main Results:
- MSI was detected in 7.8% of GBC cases, associated with loss of MMR proteins.
- No significant association between MSI and Lynch syndrome, tumor grade, or survival was found.
- Strong LINE-1 staining (hypomethylation) was absent in MSI tumors, while 52% of non-MSI tumors showed it (p=0.005), suggesting hypermethylation in MSI GBC.
- MSI tumors lacked HER2 amplification, TP53, and NRAS mutations.
Conclusions:
- MSI is a rare event in GBC, often linked to MMR protein loss potentially due to hypermethylation.
- GBC with MSI and hypermethylation represents a distinct molecular subtype.
- These findings suggest that demethylating agents could be a potential therapeutic strategy for this GBC subset.
