Multicenter Study

. 2025 May 5;24(2):44.

doi: 10.1007/s10689-025-00466-8.

Colonoscopy findings in CDH1 carriers from a multicenter international study

Arjun Chatterjee^#¹, Robert Hüneburg^#^{2

3

4}, Qijun Yang⁵, Shannon Morrison⁵, Anna Bettzüge^{2

3

4}, Tim Marwitz^{2

3

4}, Stefan Aretz^{3

4

6}, Isabel Spier^{3

4

6}, Tim Ripperger^{4

7}, Silke Redler⁸, Mykyta Kachanov^{4

9}, Alexander E Volk^{4

9}, Deepak B Vangala¹⁰, Severin Daum¹¹, Elke Holinski-Feder^{4

12

13}, Verena Steinke-Lange^{4

12

13}, Kathrin Bahlke¹⁴, Christian P Strassburg^{2

3

4}, Lady Katherine MejiaPerez¹⁵, Margaret M O'Malley¹⁶, Lisa LaGuardia^{16

17}, David Liska^{16

17}, Carole Macaron^{15

17}, Joshua Sommovilla^{16

17}, Carol A Burke^#^{18

19

20

21}, Jacob Nattermann^#^{2

3

4}

Affiliations

¹ Department of Internal Medicine, Cleveland Clinic, Cleveland, OH, USA.
² Department of Internal Medicine, University Hospital Bonn, Bonn, Germany.
³ National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.
⁴ European Reference Network for Genetic Tumor Risk Syndromes (ERN Genturis), Nijmegen, The Netherlands.
⁵ Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
⁶ Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany.
⁷ Department of Human Genetics, Hannover Medical School, Hannover, Germany.
⁸ Institute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
⁹ Institute for Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
¹⁰ Genetics, Department of Cancer Genetics, Ruhr-University Bochum, Bochum, Germany.
¹¹ Medical Department, Division of Gastroenterology, Infectious Diseases and Rheumatology, Charité University Medicine Berlin, Campus Benjamin Franklin (CBF), Berlin, Germany.
¹² MGZ - Medizinisch Genetisches Zentrum, Munich, Germany.
¹³ Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
¹⁴ Institute for Human Genetics, University Hospital Münster, Münster, Germany.
¹⁵ Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, Cleveland, OH, USA.
¹⁶ Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH, USA.
¹⁷ Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia, Cleveland Clinic, Cleveland, OH, 44195, USA.
¹⁸ Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, Cleveland, OH, USA. BURKEC1@ccf.org.
¹⁹ Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH, USA. BURKEC1@ccf.org.
²⁰ Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia, Cleveland Clinic, Cleveland, OH, 44195, USA. BURKEC1@ccf.org.
²¹ Desk A30, Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH, 44195, USA. BURKEC1@ccf.org.

^# Contributed equally.

PMID: 40323501
PMCID: PMC12052908
DOI: 10.1007/s10689-025-00466-8

Multicenter Study

Colonoscopy findings in CDH1 carriers from a multicenter international study

Arjun Chatterjee et al. Fam Cancer. 2025.

. 2025 May 5;24(2):44.

doi: 10.1007/s10689-025-00466-8.

Authors

Affiliations

¹ Department of Internal Medicine, Cleveland Clinic, Cleveland, OH, USA.
² Department of Internal Medicine, University Hospital Bonn, Bonn, Germany.
³ National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.
⁴ European Reference Network for Genetic Tumor Risk Syndromes (ERN Genturis), Nijmegen, The Netherlands.
⁵ Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
⁶ Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany.
⁷ Department of Human Genetics, Hannover Medical School, Hannover, Germany.
⁸ Institute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
⁹ Institute for Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
¹⁰ Genetics, Department of Cancer Genetics, Ruhr-University Bochum, Bochum, Germany.
¹¹ Medical Department, Division of Gastroenterology, Infectious Diseases and Rheumatology, Charité University Medicine Berlin, Campus Benjamin Franklin (CBF), Berlin, Germany.
¹² MGZ - Medizinisch Genetisches Zentrum, Munich, Germany.
¹³ Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
¹⁴ Institute for Human Genetics, University Hospital Münster, Münster, Germany.
¹⁵ Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, Cleveland, OH, USA.
¹⁶ Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH, USA.
¹⁷ Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia, Cleveland Clinic, Cleveland, OH, 44195, USA.
¹⁸ Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, Cleveland, OH, USA. BURKEC1@ccf.org.
¹⁹ Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH, USA. BURKEC1@ccf.org.
²⁰ Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia, Cleveland Clinic, Cleveland, OH, 44195, USA. BURKEC1@ccf.org.
²¹ Desk A30, Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH, 44195, USA. BURKEC1@ccf.org.

^# Contributed equally.

PMID: 40323501
PMCID: PMC12052908
DOI: 10.1007/s10689-025-00466-8

Abstract

Germline (likely-)pathogenic variants (PV) in CDH1 predispose carriers to hereditary diffuse gastric cancer and lobular breast cancer. Previous studies from the United States suggest CDH1 variant carriers have an increased risk for adenomas or sessile serrated lesions (SSL), yet data linking CDH1 PVs and colorectal neoplasia are scarce. We aimed to investigate colonoscopy findings in CDH1 PVs. Adults carrying a PV/LPV in CDH1 with ≥ 1 colonoscopy between 01/01/2004-12/31/2023 were included. Patients were sourced from the David G. Jagelman Inherited Colorectal Cancer Registries at Cleveland Clinic and the German Consortium for Familial Intestinal Cancer. 103 CDH1 PV carriers were included. Most were female (66%) and white (93.1%). The median age at first colonoscopy was 47 years. The adenoma detection rate (ADR) was 29.4% (95% CI:19.9-41.1%) in the German cohort and 48.6% (95% CI: 33.0-64.4%) in the Cleveland cohort (p = 0.055) and significantly correlated with age (< 45 years, 13.6% (95% CI: 6.40-26.7%); 45-49 years, 52.4% (95% CI: 32.4-71.7%); ≥50 years, 52.6% (95% CI: 37.3-67.5%); p < 0.001). The ADR in Cleveland was higher than the U.S. average ADR but the difference was not statistically significant (48.6% vs. 35.6%, p = 0.08), and the ADR in the German cohort (29.4%) was similar to the national German average risk screening cohort (31.3% in men, p = 0.84; 20.1% in women, p = 0.08). In our screening cohort with CDH1 PV carriers, we demonstrated an ADR of 13.5% in individuals under 45 years, similar to the ADR in patients aged 25-40 years with a family history of CRC. Overall, SSL detection rate was 9.7%. Colorectal cancer was diagnosed in 3 patients (3.2%), 2/3 with an early age of onset before the age of 50 years. This first international study provides preliminary evidence of a higher ADR in U.S. CDH1 PV carriers compared to the general population, with a high number of adenomas detected before the age of 50. This may indicate an increased CRC risk that should be explored in larger studies.

Keywords: CDH1; CDH1 pathogenic variants; Colon cancer; Colonoscopy; Colorectal cancer.

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Conflict of interest statement

Declarations. Ethical approval: This study was approved by the Cleveland Clinic IRB #21-1129 and at seven centers of the German Consortium for Familial Intestinal Cancer (GCFIC; Bonn, Bochum, Düsseldorf, Hannover, Hamburg, Münster, Berlin, München; central IRB approval No. 099/15 Bonn). Patient consent: Informed consent was obtained from all individual participants included in the study in Germany. For retrospective analysis, no written informed consent was needed in Cleveland. Competing interests: The authors declare no competing interests.

References

1. Hansford S, Kaurah P, Li-Chang H et al (2015) Hereditary diffuse gastric cancer syndrome: Cdh1 mutations and beyond. JAMA Oncol 1:23–32 - DOI - PubMed
1. Pharoah PDP, Guilford P, Caldas C (2001) Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 121:1348–1353 - DOI - PubMed
1. Xicola RM, Li S, Rodriguez N et al (2019) Clinical features and cancer risk in families with pathogenic < em > CDH1 variants irrespective of clinical criteria. J Med Genet 56:838–843 - DOI - PubMed
1. Ryan CE, Fasaye G-A, Gallanis AF et al (2024) Germline CDH1 variants and lifetime Cancer risk. JAMA 332:722–729 - DOI - PMC - PubMed
1. Adib E, El Zarif T, Nassar AH et al (2022) CDH1 germline variants are enriched in patients with colorectal cancer, gastric cancer, and breast cancer. Br J Cancer 126:797–803 - DOI - PMC - PubMed

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Colonoscopy findings in CDH1 carriers from a multicenter international study

Affiliations

Colonoscopy findings in CDH1 carriers from a multicenter international study

Authors

Affiliations

Abstract

Conflict of interest statement

References

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LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous