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Updated: Jun 5, 2026
Rare Event Detection Using Error-corrected DNA and RNA Sequencing
Published on: August 3, 2018
Frequency of deletions of EPCAM (TACSTD1) in MSH2-associated Lynch syndrome cases
Kandelaria Rumilla1, Karen V Schowalter, Noralane M Lindor
1Departments of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 59095, USA.
Abstract:
Lynch syndrome is an autosomal dominant cancer predisposition syndrome characterized by loss of function of DNA mismatch repair enzyme MLH1, MSH2, MSH6, or PMS2. Mutations in MLH1 and MSH2 account for ∼80% of the inherited cases. However, in up to 20% of cases suspected of having a germline mutation in MSH2 due to loss of MSH2 expression, a germline mutation is not identified. Recent studies have shown that some Lynch syndrome cases are due to 3' EPCAM/TACSTD1 deletions that subsequently lead to MSH2 promoter hypermethylation. In this study, we examined the frequency of this novel mechanism for MSH2 inactivation in cases recruited through the Colon Cancer Family Registry and from the Mayo Clinic Molecular Diagnostics Laboratory. From the combined cohort, 58 cases were selected in which immunohistochemical staining suggested a mutation in MSH2 or MSH6, but no mutations were identified on follow-up testing. Of these 58 cases, 11 demonstrated a deletion of EPCAM/TACSTD1. Of cases with a deletion, the methylation status of the MSH2 promoter was confirmed in tumor tissue using methylation-sensitive PCR primers. One case showed MSH2 promoter hypermethylation in the absence of a detectable EPCAM/TACSTD1 deletion. These results indicate that approximately 20% to 25% of cases suspected of having a mutation in MSH2 but in which a germline mutation is not detected, can be accounted for by germline deletions in EPCAM/TACSTD1. These data also suggest the presence of other alterations leading to MSH2 promoter hypermethylation.
Insights
Lynch syndrome, a hereditary cancer risk, often involves MSH2 gene issues. This study finds that deletions in the EPCAM gene explain many MSH2-related Lynch syndrome cases where mutations aren't found.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Lynch syndrome is an inherited cancer predisposition caused by DNA mismatch repair gene dysfunction.
- MLH1 and MSH2 mutations are common, but up to 20% of suspected MSH2 cases lack identified mutations.
- EPCAM/TACSTD1 deletions causing MSH2 promoter hypermethylation are a newly identified cause of Lynch syndrome.
Purpose of the Study:
- To investigate the frequency of EPCAM/TACSTD1 deletions causing MSH2 inactivation in Lynch syndrome.
- To analyze MSH2 promoter methylation in relation to EPCAM/TACSTD1 deletions.
Main Methods:
- Examined 58 cases with suspected MSH2/MSH6 mutations but no identified germline mutations.
- Utilized immunohistochemistry and follow-up testing.
- Assessed MSH2 promoter methylation using methylation-sensitive PCR in tumor tissue.
Main Results:
- Eleven of 58 cases (approx. 19%) showed EPCAM/TACSTD1 deletions.
- One case exhibited MSH2 promoter hypermethylation without a detectable EPCAM/TACSTD1 deletion.
- Approximately 20-25% of unexplained MSH2-related Lynch syndrome cases are attributed to EPCAM/TACSTD1 deletions.
Conclusions:
- Germline EPCAM/TACSTD1 deletions are a significant cause of MSH2 inactivation in Lynch syndrome.
- The findings highlight a novel mechanism for Lynch syndrome, impacting genetic diagnostics.
- Further research is needed to identify other causes of MSH2 promoter hypermethylation.
