TY - JOUR
T1 - Lynch syndrome-associated extracolonic tumors are rare in two extended families with the same EPCAM deletion
AU - Lynch, Henry T
AU - Riegert-Johnson, Douglas L
AU - Snyder, Carrie
AU - Lynch, Jane F
AU - Hagenkord, Jill
AU - Boland, C Richard
AU - Rhees, Jennifer
AU - Thibodeau, Stephen N
AU - Boardman, Lisa A
AU - Davies, Janine
AU - Kuiper, Roland P
AU - Hoogerbrugge, Nicoline
AU - Ligtenberg, Marjolijn J L
PY - 2011/10
Y1 - 2011/10
N2 - OBJECTIVES: The Lynch syndrome (LS) is an inherited cancer syndrome showing a preponderance of colorectal cancer (CRC) in context with endometrial cancer and several other extracolonic cancers, which is due to pathogenic mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2. Some families were found to show a LS phenotype without an identified MMR mutation, although there was microsatellite instability and absence of MSH2 expression by immunohistochemistry. Studies of a subset of these families found a deletion at the 3' end of the epithelial cell adhesion molecule (EPCAM) gene, causing transcription read-through resulting in silencing of MSH2 through hypermethylation of its promoter. The tumor spectrum of such families appears to differ from classical LS.METHODS: Our study of two large families (USA Family R and Dutch Family A) with an EPCAM deletion was carried out using each institution's standard family study protocol. DNA was extracted from peripheral blood and EPCAM deletion analysis was performed.RESULTS: Both families were found to harbor the same deletion at the 3' end of EPCAM. Analysis showed that the deletion originated from a common ancestor. Family R and Family A members showed segregation of CRC with the presence of this EPCAM mutation. Compared with classic LS, there were almost no extracolonic cancers.CONCLUSIONS: Members of Family R and Family A, all with the same EPCAM deletion, predominantly presented with CRC but no LS-associated endometrial cancer, confirming findings seen in other, smaller, LS families with EPCAM mutations. In these EPCAM mutation carriers, cancer surveillance should be focused on CRC.
AB - OBJECTIVES: The Lynch syndrome (LS) is an inherited cancer syndrome showing a preponderance of colorectal cancer (CRC) in context with endometrial cancer and several other extracolonic cancers, which is due to pathogenic mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2. Some families were found to show a LS phenotype without an identified MMR mutation, although there was microsatellite instability and absence of MSH2 expression by immunohistochemistry. Studies of a subset of these families found a deletion at the 3' end of the epithelial cell adhesion molecule (EPCAM) gene, causing transcription read-through resulting in silencing of MSH2 through hypermethylation of its promoter. The tumor spectrum of such families appears to differ from classical LS.METHODS: Our study of two large families (USA Family R and Dutch Family A) with an EPCAM deletion was carried out using each institution's standard family study protocol. DNA was extracted from peripheral blood and EPCAM deletion analysis was performed.RESULTS: Both families were found to harbor the same deletion at the 3' end of EPCAM. Analysis showed that the deletion originated from a common ancestor. Family R and Family A members showed segregation of CRC with the presence of this EPCAM mutation. Compared with classic LS, there were almost no extracolonic cancers.CONCLUSIONS: Members of Family R and Family A, all with the same EPCAM deletion, predominantly presented with CRC but no LS-associated endometrial cancer, confirming findings seen in other, smaller, LS families with EPCAM mutations. In these EPCAM mutation carriers, cancer surveillance should be focused on CRC.
KW - Adult
KW - Aged
KW - Antigens, Neoplasm/genetics
KW - Cell Adhesion Molecules/genetics
KW - Colorectal Neoplasms/genetics
KW - Colorectal Neoplasms, Hereditary Nonpolyposis/complications
KW - DNA Methylation
KW - Epithelial Cell Adhesion Molecule
KW - Female
KW - Gene Deletion
KW - Gene Silencing
KW - Humans
KW - Male
KW - Microsatellite Instability
KW - Middle Aged
KW - MutS Homolog 2 Protein/genetics
KW - Netherlands
KW - Pedigree
KW - Promoter Regions, Genetic
KW - United States
UR - http://www.scopus.com/inward/record.url?scp=80053909171&partnerID=8YFLogxK
U2 - 10.1038/ajg.2011.203
DO - 10.1038/ajg.2011.203
M3 - Article
C2 - 21769135
SN - 0002-9270
VL - 106
SP - 1829
EP - 1836
JO - The American journal of gastroenterology
JF - The American journal of gastroenterology
IS - 10
ER -