Colonoscopy findings in CDH1 carriers from a multicenter international study

TL;DR

This study finds that CDH1 gene carriers have a higher risk of colon polyps, especially before age 50, suggesting a possible increased risk of colorectal cancer.

Contribution

The study is the first international investigation of colonoscopy findings in CDH1 carriers, revealing age-related adenoma detection rates.

Findings

Adenoma detection rate was 13.5% in CDH1 carriers under 45 years, similar to those with a family history of CRC.

Colorectal cancer was diagnosed in 3.2% of CDH1 carriers, with two cases occurring before age 50.

The adenoma detection rate in the U.S. cohort was higher than the general population, though not statistically significant.

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.

The online version contains supplementary material available at 10.1007/s10689-025-00466-8.