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Article: Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: A cohort study

TitleRisk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: A cohort study
Authors
Issue Date2011
PublisherThe Lancet Publishing Group. The Journal's web site is located at http://www.elsevier.com/locate/j.lancetoncol
Citation
The Lancet Oncology, 2011, v. 12 n. 1, p. 49-55 How to Cite?
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. 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.
Persistent Identifierhttp://hdl.handle.net/10722/139919
ISSN
2013 Impact Factor: 24.725
ISI Accession Number ID
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.

References

 

DC FieldValueLanguage
dc.contributor.authorKempers, MJEen_HK
dc.contributor.authorKuiper, RPen_HK
dc.contributor.authorOckeloen, CWen_HK
dc.contributor.authorChappuis, POen_HK
dc.contributor.authorHutter, Pen_HK
dc.contributor.authorRahner, Nen_HK
dc.contributor.authorSchackert, HKen_HK
dc.contributor.authorSteinke, Ven_HK
dc.contributor.authorHolinskiFeder, Een_HK
dc.contributor.authorMorak, Men_HK
dc.contributor.authorKloor, Men_HK
dc.contributor.authorBüttner, Ren_HK
dc.contributor.authorVerwiel, ETPen_HK
dc.contributor.authorvan Krieken, JHen_HK
dc.contributor.authorNagtegaal, IDen_HK
dc.contributor.authorGoossens, Men_HK
dc.contributor.authorvan der Post, RSen_HK
dc.contributor.authorNiessen, RCen_HK
dc.contributor.authorSijmons, RHen_HK
dc.contributor.authorKluijt, Ien_HK
dc.contributor.authorHogervorst, FBLen_HK
dc.contributor.authorLeter, EMen_HK
dc.contributor.authorGille, JJPen_HK
dc.contributor.authorAalfs, CMen_HK
dc.contributor.authorRedeker, EJWen_HK
dc.contributor.authorHes, FJen_HK
dc.contributor.authorTops, CMJen_HK
dc.contributor.authorvan Nesselrooij, BPMen_HK
dc.contributor.authorvan Gijn, MEen_HK
dc.contributor.authorGarcía, EBGen_HK
dc.contributor.authorEccles, DMen_HK
dc.contributor.authorBunyan, DJen_HK
dc.contributor.authorSyngal, Sen_HK
dc.contributor.authorStoffel, EMen_HK
dc.contributor.authorCulver, JOen_HK
dc.contributor.authorPalomares, MRen_HK
dc.contributor.authorGraham, Ten_HK
dc.contributor.authorVelsher, Len_HK
dc.contributor.authorPapp, Jen_HK
dc.contributor.authorOláh, Een_HK
dc.contributor.authorChan, TLen_HK
dc.contributor.authorLeung, SYen_HK
dc.contributor.authorvan Kessel, AGen_HK
dc.contributor.authorKiemeney, LALMen_HK
dc.contributor.authorHoogerbrugge, Nen_HK
dc.contributor.authorLigtenberg, MJLen_HK
dc.date.accessioned2011-09-23T06:01:15Z-
dc.date.available2011-09-23T06:01:15Z-
dc.date.issued2011en_HK
dc.identifier.citationThe Lancet Oncology, 2011, v. 12 n. 1, p. 49-55en_HK
dc.identifier.issn1470-2045en_HK
dc.identifier.urihttp://hdl.handle.net/10722/139919-
dc.descriptionComment in Lancet Oncol. 2011 Jan;12(1):5-6.-
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.en_HK
dc.languageengen_US
dc.publisherThe Lancet Publishing Group. The Journal's web site is located at http://www.elsevier.com/locate/j.lancetoncolen_HK
dc.relation.ispartofThe Lancet Oncologyen_HK
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 studyen_HK
dc.typeArticleen_HK
dc.identifier.emailChan, TL:tlchan@hku.hken_HK
dc.identifier.emailLeung, SY:suetyi@hkucc.hku.hken_HK
dc.identifier.authorityChan, TL=rp00418en_HK
dc.identifier.authorityLeung, SY=rp00359en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/S1470-2045(10)70265-5en_HK
dc.identifier.pmid21145788en_HK
dc.identifier.scopuseid_2-s2.0-78650692633en_HK
dc.identifier.hkuros192322en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-78650692633&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume12en_HK
dc.identifier.issue1en_HK
dc.identifier.spage49en_HK
dc.identifier.epage55en_HK
dc.identifier.isiWOS:000286362100021-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.citeulike8415353-

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