Marlies Kempers

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

BACKGROUNDnLynch 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.nnnMETHODSnWe 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.nnnFINDINGSn93 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.nnnINTERPRETATIONnEPCAM 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.

An FBN1 Deep Intronic Mutation in a Familial Case of Marfan Syndrome: An Explanation for Genetically Unsolved Cases?

Marfan syndrome (MFS) is caused by mutations in the FBN1 (fibrillin‐1) gene, but approximately 10% of MFS cases remain genetically unsolved. Here, we report a new FBN1 mutation in an MFS family that had remained negative after extensive molecular genomic DNA FBN1 testing, including denaturing high‐performance liquid chromatography, Sanger sequencing, and multiplex ligation‐dependent probe amplification. Linkage analysis in the family and cDNA sequencing of the proband revealed a deep intronic point mutation in intron 56 generating a new splice donor site. This mutation results in the integration of a 90‐bp pseudo‐exon between exons 56 and 57 containing a stop codon, causing nonsense‐mediated mRNA decay. Although more than 90% of FBN1 mutations can be identified with regular molecular testing at the genomic level, deep intronic mutations will be missed and require cDNA sequencing or whole‐genome sequencing.

A clinical appraisal of different Z -score equations for aortic root assessment in the diagnostic evaluation of Marfan syndrome

Purpose:Aortic sinus diameter dilatation expressed as a Z-score >2.0 is diagnostic in Marfan syndrome. In addition to the classic equation (Z1) for calculating Z-scores, two new equations were recently introduced (Z2 and Z3).Methods:We studied the effects of obesity, age, and the absolute cut point of 40u2009mm on these three equations in 2,674 echocardiographic measurements of 260 patients with Marfan syndrome.Results:Diameters ≥40u2009mm were associated with Z1 scores <2.0 in 109 measurements (11.0%; 35 patients), Z2 scores <2.0 in 37 measurements (3.8%; 13 patients), and Z3 scores <2.0 in 24 measurements (2.4%; 11 patients). Mean diameters increased after the 40th birthday: 42.0 (37.3–44.8u2009mm interquartile range) to 42.5 (39.0–45.0u2009mm interquartile range; P = not significant) and mean Z1 scores decreased from 3.60 to 2.17 (P < 0.01), whereas Z2 and Z3 scores tended to increase (Z2: 3.04–3.27; Z3: 3.39–3.55; P = not significant for both). Comparing Z-scores between patients with body mass index <25u2009kg/m² (group A) and those with body mass index ≥25u2009kg/m² (group B), median Z1 scores differed between groups (Z1 = 3.00 in group A, Z1 = 1.78 in group B; P = 0.012), whereas Z2 (Z2 = 2.82 in group A, Z2 = 2.47 in group B; P = 0.52) and Z3 scores (Z3 = 2.72 in group A, Z2 = 3.12 in group B; P = 0.32) did not.Conclusion:Z1 scores are inferior to Z2 and Z3 scores in Marfan syndrome. In particular, the Z3 score, correcting aortic sinus diameter for body height, seems excellent.Genet Med 2013:15(7):528–532

HIGH COLORECTAL AND LOW ENDOMETRIAL CANCER RISK IN EPCAM DELETION-POSITIVE LYNCH SYNDROME: A COHORT STUDY

BACKGROUNDnLynch 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.nnnMETHODSnWe 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.nnnFINDINGSn93 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.nnnINTERPRETATIONnEPCAM 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.

Abstract A37: MSI is not an important feature in early onset pancreatic carcinoma

Background and Aim: There is scant information on pancreatic cancer occurring at young age. About 5 to 10 percent of patients with pancreatic cancer have a family history of pancreatic cancer, which is partially due to defined hereditary syndromes like Lynch syndrome. Recently, we have identified deletions of the 3’ end of the EPCAM gene as a novel cause of this hereditary syndrome. In the cohort of patients with EPCAM deletions a relatively high number of pancreatic cancers and duodenal cancers were observed. We therefore aimed to assess whether development of pancreatic or duodenal cancer at young age might be an indication of EPCAM-associated Lynch syndrome. Methods: We searched the Dutch Pathology Registry (PALGA) to identify all patients who were diagnosed with pancreatic carcinoma (PC), ampulla of Vater carcinoma (VC) or duodenal carcinoma (DC) before the age of 50 in The Netherlands between January 2000 and December 2012. Immunohistochemical analysis was used to analyze mismatch repair (MMR)- and EPCAM-protein expression. MS-status was determined by a panel of 5 mononucleotide repeats in cases with an aberrant MMR protein pattern. Furthermore, multiplex ligation-dependent probe amplification will be performed in case of an absent EPCAM staining or loss of MSH2 and MSH6 protein expression. Results: An aberrant MMR-IHC for PMS2 combined with microsatellite instability (MSI) was identified in 1 of 48 (2%) PC diagnosed before age 50. In 24 VC patients, one tumor (4%) showed MSI with absence of both MLH1 and PMS2 staining. This patient had a history of colon carcinoma at the age of 43 years. All patients showed a normal immunohistochemical staining for MSH2 and MSH6. EPCAM protein expression was present in all cases, except one case with an anaplastic pancreas carcinoma where EPCAM was absent in the vimentine-positive area of the tumor. Eight out of 22 DC tumors (36%) showed a MMR-defective phenotype with MSI, of which 2 with an aberrant MSH2 and MSH6 staining and a positive EPCAM protein expression. One of these two patients had a history of colon carcinoma at the age of 24 and 26 years. Conclusion: This nationwide study cohort suggests that early onset pancreatic cancer and ampulla of Vater cancer are at most rarely associated with (EPCAM-associated) Lynch syndrome, in contrast to early onset duodenal cancer. Citation Format: Monica AJ Van Zanten, Marlies JE Kempers, Marjolijn JL Ligtenberg, Iris D. Nagtegaal. MSI is not an important feature in early onset pancreatic carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A37.

Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome

BACKGROUNDnLynch 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.nnnMETHODSnWe 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.nnnFINDINGSn93 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.nnnINTERPRETATIONnEPCAM 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.