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Article: Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: A cohort study
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TitleRisk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: A cohort study
 
AuthorsKempers, MJE18
Kuiper, RP18
Ockeloen, CW18
Chappuis, PO8
Hutter, P10
Rahner, N2
Schackert, HK4
Steinke, V2
HolinskiFeder, E1
Morak, M1
Kloor, M19
Büttner, R2
Verwiel, ETP18
van Krieken, JH18
Nagtegaal, ID18
Goossens, M18
van der Post, RS18
Niessen, RC9
Sijmons, RH9
Kluijt, I6
Hogervorst, FBL6
Leter, EM11
Gille, JJP11
Aalfs, CM5
Redeker, EJW5
Hes, FJ20
Tops, CMJ20
van Nesselrooij, BPM
van Gijn, ME
García, EBG13
Eccles, DM17
Bunyan, DJ3
Syngal, S12
Stoffel, EM12
Culver, JO15
Palomares, MR15
Graham, T16
Velsher, L16
Papp, J14
Oláh, E14
Chan, TL7
Leung, SY7
van Kessel, AG18
Kiemeney, LALM18
Hoogerbrugge, N18
Ligtenberg, MJL18
 
Issue Date2011
 
PublisherThe Lancet Publishing Group. The Journal's web site is located at http://www.elsevier.com/locate/j.lancetoncol
 
CitationThe Lancet Oncology, 2011, v. 12 n. 1, p. 49-55 [How to Cite?]
DOI: http://dx.doi.org/10.1016/S1470-2045(10)70265-5
 
AbstractBackground: 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. Findings: 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. Interpretation: 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. Funding: Sacha Swarttouw-Hijmans Foundation, Dutch Cancer Society, Deutsche Krebshilfe (German Cancer Aid), Hong Kong Cancer Fund, Hungarian Research Grant OTKA, Norwegian EEA Financial Mechanism (Hungarian National Institute of Oncology), and US National Cancer Institute. © 2011 Elsevier Ltd.
 
DescriptionComment in Lancet Oncol. 2011 Jan;12(1):5-6.
 
ISSN1470-2045
2013 Impact Factor: 24.725
 
DOIhttp://dx.doi.org/10.1016/S1470-2045(10)70265-5
 
ISI Accession Number IDWOS:000286362100021
Funding AgencyGrant Number
Sacha Swarttouw-Hijmans Foundation
Dutch Cancer Society2009-4335
Deutsche Krebshilfe (German Cancer Aid)
Hong Kong Cancer Fund
Hungarian Research Grant OTKA
Norwegian EEA Financial Mechanism (Hungarian National Institute of Oncology)
US National Cancer InstituteRC4CA153828
Hungarian Research GrantNKTH-OTKA K-80745
Norwegian EEA Financial MechanismHu0115/NA/2008-3/OP-9
Funding Information:

Funding Sacha Swarttouw-Hijmans Foundation, Dutch Cancer Society, Deutsche Krebshilfe (German Cancer Aid), Hong Kong Cancer Fund, Hungarian Research Grant OTKA, Norwegian EEA Financial Mechanism (Hungarian National Institute of Oncology), and US National Cancer Institute.We thank the families and their counsellors who contributed to this study. The study was supported by unrestricted grants from the the Sacha Swarttouw-Hijmans foundation, the Dutch Cancer Society grant 2009-4335, the Deutsche Krebshilfe (German Cancer Aid), the Hong Kong Cancer Fund, the Hungarian Research Grant NKTH-OTKA K-80745, and the Norwegian EEA Financial Mechanism Hu0115/NA/2008-3/OP-9. The City of Hope Hereditary Cancer Registry is supported in part by award number RC4CA153828 from the US National Cancer Institute.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorKempers, MJE
 
dc.contributor.authorKuiper, RP
 
dc.contributor.authorOckeloen, CW
 
dc.contributor.authorChappuis, PO
 
dc.contributor.authorHutter, P
 
dc.contributor.authorRahner, N
 
dc.contributor.authorSchackert, HK
 
dc.contributor.authorSteinke, V
 
dc.contributor.authorHolinskiFeder, E
 
dc.contributor.authorMorak, M
 
dc.contributor.authorKloor, M
 
dc.contributor.authorBüttner, R
 
dc.contributor.authorVerwiel, ETP
 
dc.contributor.authorvan Krieken, JH
 
dc.contributor.authorNagtegaal, ID
 
dc.contributor.authorGoossens, M
 
dc.contributor.authorvan der Post, RS
 
dc.contributor.authorNiessen, RC
 
dc.contributor.authorSijmons, RH
 
dc.contributor.authorKluijt, I
 
dc.contributor.authorHogervorst, FBL
 
dc.contributor.authorLeter, EM
 
dc.contributor.authorGille, JJP
 
dc.contributor.authorAalfs, CM
 
dc.contributor.authorRedeker, EJW
 
dc.contributor.authorHes, FJ
 
dc.contributor.authorTops, CMJ
 
dc.contributor.authorvan Nesselrooij, BPM
 
dc.contributor.authorvan Gijn, ME
 
dc.contributor.authorGarcía, EBG
 
dc.contributor.authorEccles, DM
 
dc.contributor.authorBunyan, DJ
 
dc.contributor.authorSyngal, S
 
dc.contributor.authorStoffel, EM
 
dc.contributor.authorCulver, JO
 
dc.contributor.authorPalomares, MR
 
dc.contributor.authorGraham, T
 
dc.contributor.authorVelsher, L
 
dc.contributor.authorPapp, J
 
dc.contributor.authorOláh, E
 
dc.contributor.authorChan, TL
 
dc.contributor.authorLeung, SY
 
dc.contributor.authorvan Kessel, AG
 
dc.contributor.authorKiemeney, LALM
 
dc.contributor.authorHoogerbrugge, N
 
dc.contributor.authorLigtenberg, MJL
 
dc.date.accessioned2011-09-23T06:01:15Z
 
dc.date.available2011-09-23T06:01:15Z
 
dc.date.issued2011
 
dc.description.abstractBackground: 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. Findings: 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. Interpretation: 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. Funding: Sacha Swarttouw-Hijmans Foundation, Dutch Cancer Society, Deutsche Krebshilfe (German Cancer Aid), Hong Kong Cancer Fund, Hungarian Research Grant OTKA, Norwegian EEA Financial Mechanism (Hungarian National Institute of Oncology), and US National Cancer Institute. © 2011 Elsevier Ltd.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.descriptionComment in Lancet Oncol. 2011 Jan;12(1):5-6.
 
dc.identifier.citationThe Lancet Oncology, 2011, v. 12 n. 1, p. 49-55 [How to Cite?]
DOI: http://dx.doi.org/10.1016/S1470-2045(10)70265-5
 
dc.identifier.citeulike8415353
 
dc.identifier.doihttp://dx.doi.org/10.1016/S1470-2045(10)70265-5
 
dc.identifier.epage55
 
dc.identifier.hkuros192322
 
dc.identifier.isiWOS:000286362100021
Funding AgencyGrant Number
Sacha Swarttouw-Hijmans Foundation
Dutch Cancer Society2009-4335
Deutsche Krebshilfe (German Cancer Aid)
Hong Kong Cancer Fund
Hungarian Research Grant OTKA
Norwegian EEA Financial Mechanism (Hungarian National Institute of Oncology)
US National Cancer InstituteRC4CA153828
Hungarian Research GrantNKTH-OTKA K-80745
Norwegian EEA Financial MechanismHu0115/NA/2008-3/OP-9
Funding Information:

Funding Sacha Swarttouw-Hijmans Foundation, Dutch Cancer Society, Deutsche Krebshilfe (German Cancer Aid), Hong Kong Cancer Fund, Hungarian Research Grant OTKA, Norwegian EEA Financial Mechanism (Hungarian National Institute of Oncology), and US National Cancer Institute.We thank the families and their counsellors who contributed to this study. The study was supported by unrestricted grants from the the Sacha Swarttouw-Hijmans foundation, the Dutch Cancer Society grant 2009-4335, the Deutsche Krebshilfe (German Cancer Aid), the Hong Kong Cancer Fund, the Hungarian Research Grant NKTH-OTKA K-80745, and the Norwegian EEA Financial Mechanism Hu0115/NA/2008-3/OP-9. The City of Hope Hereditary Cancer Registry is supported in part by award number RC4CA153828 from the US National Cancer Institute.

 
dc.identifier.issn1470-2045
2013 Impact Factor: 24.725
 
dc.identifier.issue1
 
dc.identifier.pmid21145788
 
dc.identifier.scopuseid_2-s2.0-78650692633
 
dc.identifier.spage49
 
dc.identifier.urihttp://hdl.handle.net/10722/139919
 
dc.identifier.volume12
 
dc.languageeng
 
dc.publisherThe Lancet Publishing Group. The Journal's web site is located at http://www.elsevier.com/locate/j.lancetoncol
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofThe Lancet Oncology
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshAntigens, Neoplasm - genetics
 
dc.subject.meshCell Adhesion Molecules - genetics
 
dc.subject.meshColorectal Neoplasms - etiology - genetics
 
dc.subject.meshEndometrial Neoplasms - etiology - genetics
 
dc.subject.meshSequence Deletion
 
dc.titleRisk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: A cohort study
 
dc.typeArticle
 
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<contributor.author>Kuiper, RP</contributor.author>
<contributor.author>Ockeloen, CW</contributor.author>
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<contributor.author>Rahner, N</contributor.author>
<contributor.author>Schackert, HK</contributor.author>
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<contributor.author>Morak, M</contributor.author>
<contributor.author>Kloor, M</contributor.author>
<contributor.author>B&#252;ttner, R</contributor.author>
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<contributor.author>Eccles, DM</contributor.author>
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<contributor.author>Hoogerbrugge, N</contributor.author>
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<date.available>2011-09-23T06:01:15Z</date.available>
<date.issued>2011</date.issued>
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<description.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&apos; 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&apos; 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. Findings: 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&#183;8609) or mutations in MSH2 (77% [64-90], p=0&#183;5892) or MLH1 (79% [68-90], p=0&#183;5492), but was higher than noted for carriers of MSH6 mutation (50% [38-62], p&lt;0&#183;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&lt;0&#183;0001) or of a mutation in MSH2 (51% [33-69], p=0&#183;0006) or MSH6 (34% [20-48], p=0&#183;0309), but did not differ significantly from that noted for MLH1 (33% [15-51], p=0&#183;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. Interpretation: 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. Funding: Sacha Swarttouw-Hijmans Foundation, Dutch Cancer Society, Deutsche Krebshilfe (German Cancer Aid), Hong Kong Cancer Fund, Hungarian Research Grant OTKA, Norwegian EEA Financial Mechanism (Hungarian National Institute of Oncology), and US National Cancer Institute. &#169; 2011 Elsevier Ltd.</description.abstract>
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Author Affiliations
  1. Ludwig-Maximilians-Universität München
  2. Universität Bonn
  3. Salisbury District Hospital
  4. Technische Universität Dresden
  5. Academic Medical Centre, University of Amsterdam
  6. The Netherlands Cancer Institute
  7. The University of Hong Kong
  8. Hôpitaux universitaires de Genève
  9. Universitair Medisch Centrum Groningen
  10. Institut Central des Hôpitaux Valaisans
  11. VU University Medical Center
  12. Dana-Farber Cancer Institute
  13. University Medical Centre
  14. Országos Onkológiai Intézet Budapest
  15. City of Hope National Med Center
  16. null
  17. Southampton University Hospitals NHS Trust
  18. Radboud University Nijmegen Medical Centre
  19. null
  20. Leiden University Medical Center - LUMC