title: Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study.
abstract: BACKGROUND
  Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch-repair genes and leads to a high risk of colorectal and endometrial cancer. We previously showed that constitutional 3' end deletions of EPCAM can cause Lynch syndrome through epigenetic silencing of MSH2 in EPCAM-expressing tissues, resulting in tissue-specific MSH2 deficiency. We aim to establish the risk of cancer associated with such EPCAM deletions.
  
  
  METHODS
  We obtained clinical data for 194 carriers of a 3' end EPCAM deletion from 41 families known to us at the Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands and compared cancer risk with data from a previously described cohort of 473 carriers from 91 families with mutations in MLH1, MSH2, MSH6, or a combined EPCAM-MSH2 deletion.
  
  
  RESULTS
  93 of the 194 EPCAM deletion carriers were diagnosed with colorectal cancer; three of the 92 women with EPCAM deletions were diagnosed with endometrial cancer. Carriers of an EPCAM deletion had a 75% (95% CI 65-85) cumulative risk of colorectal cancer before the age of 70 years (mean age at diagnosis 43 years [SD 12]), which did not differ significantly from that of carriers of combined EPCAM-MSH2 deletion (69% [95% CI 47-91], p=0·8609) or mutations in MSH2 (77% [64-90], p=0·5892) or MLH1 (79% [68-90], p=0·5492), but was higher than noted for carriers of MSH6 mutation (50% [38-62], p<0·0001). By contrast, women with EPCAM deletions had a 12% [0-27] cumulative risk of endometrial cancer, which was lower than was that noted for carriers of a combined EPCAM-MSH2 deletion (55% [20-90], p<0·0001) or of a mutation in MSH2 (51% [33-69], p=0·0006) or MSH6 (34% [20-48], p=0·0309), but did not differ significantly from that noted for MLH1 (33% [15-51], p=0·1193) mutation carriers. This risk seems to be restricted to deletions that extend close to the MSH2 gene promoter. Of 194 carriers of an EPCAM deletion, three had duodenal cancer and four had pancreatic cancer.
  
  
  CONCLUSIONS
  EPCAM deletion carriers have a high risk of colorectal cancer; only those with deletions extending close to the MSH2 promoter have an increased risk of endometrial cancer. These results underscore the effect of mosaic MSH2 deficiency, leading to variable cancer risks, and could form the basis of an optimised protocol for the recognition and targeted prevention of cancer in EPCAM deletion carriers.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
authors.forename: Marlies J E
authors.initials: MJ
authors.lastname: Kempers
authors.forename: Roland P
authors.initials: RP
authors.lastname: Kuiper
authors.forename: Charlotte W
authors.initials: CW
authors.lastname: Ockeloen
authors.forename: Pierre O
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authors.lastname: Chappuis
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authors.lastname: Hutter
authors.forename: Nils
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authors.forename: Hans K
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authors.forename: Verena
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authors.lastname: Büttner
authors.forename: Eugene T P
authors.initials: ET
authors.lastname: Verwiel
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authors.initials: JH
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authors.lastname: Nagtegaal
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authors.lastname: Goossens
authors.forename: Rachel S
authors.initials: RS
authors.lastname: van der Post
authors.forename: Renée C
authors.initials: RC
authors.lastname: Niessen
authors.forename: Rolf H
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authors.lastname: Sijmons
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authors.lastname: Kluijt
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authors.initials: FB
authors.lastname: Hogervorst
authors.forename: Edward M
authors.initials: EM
authors.lastname: Leter
authors.forename: Johan J P
authors.initials: JJ
authors.lastname: Gille
authors.forename: Cora M
authors.initials: CM
authors.lastname: Aalfs
authors.forename: Egbert J W
authors.initials: EJ
authors.lastname: Redeker
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: Hes
authors.forename: Carli M J
authors.initials: CM
authors.lastname: Tops
authors.forename: Bernadette P M
authors.initials: BP
authors.lastname: van Nesselrooij
authors.forename: Marielle E
authors.initials: ME
authors.lastname: van Gijn
authors.forename: Encarna B
authors.initials: EB
authors.lastname: Gómez García
authors.forename: Diana M
authors.initials: DM
authors.lastname: Eccles
authors.forename: David J
authors.initials: DJ
authors.lastname: Bunyan
authors.forename: Sapna
authors.initials: S
authors.lastname: Syngal
authors.forename: Elena M
authors.initials: EM
authors.lastname: Stoffel
authors.forename: Julie O
authors.initials: JO
authors.lastname: Culver
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Palomares
authors.forename: Tracy
authors.initials: T
authors.lastname: Graham
authors.forename: Lea
authors.initials: L
authors.lastname: Velsher
authors.forename: Janos
authors.initials: J
authors.lastname: Papp
authors.forename: Edith
authors.initials: E
authors.lastname: Oláh
authors.forename: Tsun L
authors.initials: TL
authors.lastname: Chan
authors.forename: Suet Y
authors.initials: SY
authors.lastname: Leung
authors.forename: Ad Geurts
authors.initials: AG
authors.lastname: van Kessel
authors.forename: Lambertus A L M
authors.initials: LA
authors.lastname: Kiemeney
authors.forename: Nicoline
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authors.lastname: Hoogerbrugge
authors.forename: Marjolijn J L
authors.initials: MJ
authors.lastname: Ligtenberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000209:etiology / Q000235:genetics*; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008297:Male; D008875:Middle Aged; D051718:MutS Homolog 2 Protein / Q000235:genetics; D011401:Promoter Regions, Genetic; D012306:Risk; D017384:Sequence Deletion
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein