TY - JOUR
T1 - Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome
T2 - a cohort study
AU - Kempers, Marlies J. E.
AU - Kuiper, Roland P.
AU - Ockeloen, Charlotte W.
AU - Chappuis, Pierre O.
AU - Hutter, Pierre
AU - Rahner, Nils
AU - Schackert, Hans K.
AU - Steinke, Verena
AU - Holinski-Feder, Elke
AU - Morak, Monika
AU - Kloor, Matthias
AU - Buettner, Reinhard
AU - Verwiel, Eugene T. P.
AU - van Krieken, J. Han
AU - Nagtegaal, Iris D.
AU - Goossens, Monique
AU - van der Post, Rachel S.
AU - Niessen, Renee C.
AU - Sijmons, Rolf H.
AU - Kluijt, Irma
AU - Hogervorst, Frans B. L.
AU - Leter, Edward M.
AU - Gille, Johan J. P.
AU - Aalfs, Cora M.
AU - Redeker, Egbert J. W.
AU - Hes, Frederik J.
AU - Tops, Carli M. J.
AU - van Nesselrooij, Bernadette P. M.
AU - van Gijn, Marielle E.
AU - Garcia, Encarna B. Gomez
AU - Eccles, Diana M.
AU - Bunyan, David J.
AU - Syngal, Sapna
AU - Stoffel, Elena M.
AU - Culver, Julie O.
AU - Palomares, Melanie R.
AU - Graham, Tracy
AU - Velsher, Lea
AU - Papp, Janos
AU - Olah, Edith
AU - Chan, Tsun L.
AU - Leung, Suet Y.
AU - van Kessel, Ad Geurts
AU - Kiemeney, Lambertus A. L. M.
AU - Hoogerbrugge, Nicoline
AU - Ligtenberg, Marjolijn J. L.
PY - 2011/1
Y1 - 2011/1
N2 - 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], pInterpretation 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.
AB - 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], pInterpretation 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.
KW - REPAIR GENE HMSH2
KW - MUTATION CARRIERS
KW - STEM-CELLS
KW - MSH2
KW - FAMILIES
KW - HYPERMETHYLATION
KW - SURVEILLANCE
KW - METHYLATION
KW - MANAGEMENT
KW - TACSTD1
U2 - 10.1016/S1470-2045(10)70265-5
DO - 10.1016/S1470-2045(10)70265-5
M3 - Article
SN - 1470-2045
VL - 12
SP - 49
EP - 55
JO - Lancet Oncology
JF - Lancet Oncology
IS - 1
ER -