TY - JOUR
T1 - Frequency of deletions of EPCAM (TACSTD1) in MSH2-associated Lynch syndrome cases
AU - Rumilla, Kandelaria
AU - Schowalter, Karen V.
AU - Lindor, Noralane M.
AU - Thomas, Brittany C.
AU - Mensink, Kara A.
AU - Gallinger, Steven
AU - Holter, Spring
AU - Newcomb, Polly A.
AU - Potter, John D.
AU - Jenkins, Mark A.
AU - Hopper, John L.
AU - Long, Tiffany I.
AU - Weisenberger, Daniel J.
AU - Haile, Robert W.
AU - Casey, Graham
AU - Laird, Peter W.
AU - Le Marchand, Loic
AU - Thibodeau, Stephen N.
N1 - Funding Information:
Supported by the National Cancer Institute, National Institutes of Health under RFA #CA-95-011 and through cooperative agreements with the members of the Colon Cancer Family Registry (CFR) and PIs. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the CFRs, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CFR. Collaborating centers include the Australian Colorectal Cancer Family Registry (UO1 CA097735), the USC Familial Colorectal Neoplasia Collaborative Group (UO1 CA074799), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (UO1 CA074800), Ontario Registry for Studies of Familial Colorectal Cancer (UO1 CA074783), Seattle Colorectal Cancer Family Registry (UO1 CA074794), University of Hawaii Colorectal Cancer Family Registry (UO1 CA074806), and University of California, Irvine Informatics Center (UO1 CA078296).
PY - 2011/1
Y1 - 2011/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.jmoldx.2010.11.011
DO - 10.1016/j.jmoldx.2010.11.011
M3 - Article
C2 - 21227399
AN - SCOPUS:78651074177
SN - 1525-1578
VL - 13
SP - 93
EP - 99
JO - Journal of Molecular Diagnostics
JF - Journal of Molecular Diagnostics
IS - 1
ER -