Lynch syndrome-associated extracolonic tumors are rare in two extended families with the same EPCAM deletion

Henry T. Lynch, Douglas L. Riegert-Johnson, Carrie Snyder, Jane F. Lynch, Jill Hagenkord, C. Richard Boland, Jennifer Rhees, Stephen N. Thibodeau, Lisa A. Boardman, Janine Davies, Roland P. Kuiper, Nicoline Hoogerbrugge, Marjolijn J L Ligtenberg

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Abstract

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.

Original languageEnglish
Pages (from-to)1829-1836
Number of pages8
JournalAmerican Journal of Gastroenterology
Volume106
Issue number10
DOIs
StatePublished - Oct 2011

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Hereditary Nonpolyposis Colorectal Neoplasms
Neoplasms
Colorectal Neoplasms
Mutation
DNA Mismatch Repair
Endometrial Neoplasms
Epithelial Cell Adhesion Molecule
Microsatellite Instability
Genes

All Science Journal Classification (ASJC) codes

  • Gastroenterology

Cite this

Lynch, H. T., Riegert-Johnson, D. L., Snyder, C., Lynch, J. F., Hagenkord, J., Boland, C. R., ... Ligtenberg, M. J. L. (2011). Lynch syndrome-associated extracolonic tumors are rare in two extended families with the same EPCAM deletion. American Journal of Gastroenterology, 106(10), 1829-1836. https://doi.org/10.1038/ajg.2011.203

Lynch syndrome-associated extracolonic tumors are rare in two extended families with the same EPCAM deletion. / Lynch, Henry T.; Riegert-Johnson, Douglas L.; Snyder, Carrie; Lynch, Jane F.; Hagenkord, Jill; Boland, C. Richard; Rhees, Jennifer; Thibodeau, Stephen N.; Boardman, Lisa A.; Davies, Janine; Kuiper, Roland P.; Hoogerbrugge, Nicoline; Ligtenberg, Marjolijn J L.

In: American Journal of Gastroenterology, Vol. 106, No. 10, 10.2011, p. 1829-1836.

Research output: Contribution to journalArticle

Lynch, HT, Riegert-Johnson, DL, Snyder, C, Lynch, JF, Hagenkord, J, Boland, CR, Rhees, J, Thibodeau, SN, Boardman, LA, Davies, J, Kuiper, RP, Hoogerbrugge, N & Ligtenberg, MJL 2011, 'Lynch syndrome-associated extracolonic tumors are rare in two extended families with the same EPCAM deletion', American Journal of Gastroenterology, vol. 106, no. 10, pp. 1829-1836. https://doi.org/10.1038/ajg.2011.203
Lynch, Henry T. ; Riegert-Johnson, Douglas L. ; Snyder, Carrie ; Lynch, Jane F. ; Hagenkord, Jill ; Boland, C. Richard ; Rhees, Jennifer ; Thibodeau, Stephen N. ; Boardman, Lisa A. ; Davies, Janine ; Kuiper, Roland P. ; Hoogerbrugge, Nicoline ; Ligtenberg, Marjolijn J L. / Lynch syndrome-associated extracolonic tumors are rare in two extended families with the same EPCAM deletion. In: American Journal of Gastroenterology. 2011 ; Vol. 106, No. 10. pp. 1829-1836.
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abstract = "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.",
author = "Lynch, {Henry T.} and Riegert-Johnson, {Douglas L.} and Carrie Snyder and Lynch, {Jane F.} and Jill Hagenkord and Boland, {C. Richard} and Jennifer Rhees and Thibodeau, {Stephen N.} and Boardman, {Lisa A.} and Janine Davies and Kuiper, {Roland P.} and Nicoline Hoogerbrugge and Ligtenberg, {Marjolijn J L}",
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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

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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.

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