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EPCAM mutation update : Variants associated with congenital tufting enteropathy and Lynch syndrome

Pathak, Sagar J.; Mueller, James L.; Okamoto, Kevin; Das, Barun; Hertecant, Jozef; Greenhalgh, Lynn; Cole, Trevor; Pinsk, Vered; Yerushalmi, Baruch and Gurkan, Odul E., et al. (2019) In Human Mutation 40(2). p.142-161
Abstract

The epithelial cell adhesion molecule gene (EPCAM, previously known as TACSTD1 or TROP1) encodes a membrane-bound protein that is localized to the basolateral membrane of epithelial cells and is overexpressed in some tumors. Biallelic mutations in EPCAM cause congenital tufting enteropathy (CTE), which is a rare chronic diarrheal disorder presenting in infancy. Monoallelic deletions of the 3′ end of EPCAM that silence the downstream gene, MSH2, cause a form of Lynch syndrome, which is a cancer predisposition syndrome associated with loss of DNA mismatch repair. Here, we report 13 novel EPCAM mutations from 17 CTE patients from two separate centers, review EPCAM mutations associated with CTE and Lynch syndrome, and structurally model... (More)

The epithelial cell adhesion molecule gene (EPCAM, previously known as TACSTD1 or TROP1) encodes a membrane-bound protein that is localized to the basolateral membrane of epithelial cells and is overexpressed in some tumors. Biallelic mutations in EPCAM cause congenital tufting enteropathy (CTE), which is a rare chronic diarrheal disorder presenting in infancy. Monoallelic deletions of the 3′ end of EPCAM that silence the downstream gene, MSH2, cause a form of Lynch syndrome, which is a cancer predisposition syndrome associated with loss of DNA mismatch repair. Here, we report 13 novel EPCAM mutations from 17 CTE patients from two separate centers, review EPCAM mutations associated with CTE and Lynch syndrome, and structurally model pathogenic missense mutations. Statistical analyses indicate that the c.499dupC (previously reported as c.498insC) frameshift mutation was associated with more severe treatment regimens and greater mortality in CTE, whereas the c.556-14A>G and c.491+1G>A splice site mutations were not correlated with treatments or outcomes significantly different than random simulation. These findings suggest that genotype–phenotype correlations may be useful in contributing to management decisions of CTE patients. Depending on the type and nature of EPCAM mutation, one of two unrelated diseases may occur, CTE or Lynch syndrome.

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@article{5db0478c-0272-4ea0-b452-624f3ef9be6a,
  abstract     = {<p>The epithelial cell adhesion molecule gene (EPCAM, previously known as TACSTD1 or TROP1) encodes a membrane-bound protein that is localized to the basolateral membrane of epithelial cells and is overexpressed in some tumors. Biallelic mutations in EPCAM cause congenital tufting enteropathy (CTE), which is a rare chronic diarrheal disorder presenting in infancy. Monoallelic deletions of the 3′ end of EPCAM that silence the downstream gene, MSH2, cause a form of Lynch syndrome, which is a cancer predisposition syndrome associated with loss of DNA mismatch repair. Here, we report 13 novel EPCAM mutations from 17 CTE patients from two separate centers, review EPCAM mutations associated with CTE and Lynch syndrome, and structurally model pathogenic missense mutations. Statistical analyses indicate that the c.499dupC (previously reported as c.498insC) frameshift mutation was associated with more severe treatment regimens and greater mortality in CTE, whereas the c.556-14A&gt;G and c.491+1G&gt;A splice site mutations were not correlated with treatments or outcomes significantly different than random simulation. These findings suggest that genotype–phenotype correlations may be useful in contributing to management decisions of CTE patients. Depending on the type and nature of EPCAM mutation, one of two unrelated diseases may occur, CTE or Lynch syndrome.</p>},
  author       = {Pathak, Sagar J. and Mueller, James L. and Okamoto, Kevin and Das, Barun and Hertecant, Jozef and Greenhalgh, Lynn and Cole, Trevor and Pinsk, Vered and Yerushalmi, Baruch and Gurkan, Odul E. and Yourshaw, Michael and Hernandez, Erick and Oesterreicher, Sandy and Naik, Sandhia and Sanderson, Ian R. and Axelsson, Irene and Agardh, Daniel and Boland, C. Richard and Martin, Martin G. and Putnam, Christopher D. and Sivagnanam, Mamata},
  issn         = {1059-7794},
  keyword      = {congenital tufting enteropathy,EPCAM,genotype-phenotype correlation,in silico simulation,Lynch syndrome,protein modeling},
  language     = {eng},
  number       = {2},
  pages        = {142--161},
  publisher    = {John Wiley & Sons},
  series       = {Human Mutation},
  title        = {EPCAM mutation update : Variants associated with congenital tufting enteropathy and Lynch syndrome},
  url          = {http://dx.doi.org/10.1002/humu.23688},
  volume       = {40},
  year         = {2019},
}