Association Between CDH1 Pathogenic and Likely Pathogenic Variants, Orofacial Cleft, and Cancer History

Anna Duemler, Grace-Ann Fasaye, Kathleen Calzone, Jeremy Davis Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health

Introduction: The CDH1 gene codes for epithelial cadherin protein(E-cadherin) production which is involved in calcium dependent cell adhesion and protein interactions for normal craniofacial development and tumor suppression. CDH1 pathogenic and likely pathogenic (P/LP) variants are associated with non-syndromic cleft lip and/or palate(CL/P); Blepharocheilodontic syndrome(characterized by eyelid malformations, CL/P and ectodermal dysplasia); Hereditary Diffuse Gastric Cancer(HDGC); and Hereditary Lobular Breast Cancer (HLBC). HDGC/HLBC with CL/P has been seen in case reports, with a frequency of ~3%, but there are no wide scale comprehensive studies. Limited studies show an increased rate of CL/P in families who also have gastric cancer compared to families without gastric cancer. The CDH1 variant types in families with both CL/P and HDGC/HLBC is not well characterized. The aim of this study is to better understand the association between CDH1 and HDGC/HLBC with CL/P.

Methods: The National Cancer Institute has been enrolling hereditary gastric cancer families nationwide into a natural history study since 2017. Demographic data, genotype, medical history, family history, and cancer pathology are collected. Updates to clinical information reported at enrollment are currently being updated via telephone. Descriptive statistics were used to characterize personal and cancer family history in HDGC/HLBC families with CDH1 P/LP variants confirmed in ClinVar.

Results: There are 136 families enrolled with a P/LP CDH1 variant. 15%(20/136) of families have >1 relative(s) affected by CL/P(range 1- 5, median 1). CDH1 P/LP variants found in families with CL/P include 35%(7/20) nonsense, 35%(7/20) canonical splice, 20%(4/20) large deletion of one or more exons, and 10%(2/20) cryptic splice. In total there were 30 individuals with CL/P, 60%(18/30) being men and 40%(12/30) women. 27%(8/30) of individuals with CL/P had only gastric cancer, 3/30(10%) had both gastric and breast cancer, 1/30(3%) had only breast cancer and 18/30(60%) were unaffected.

Conclusions: CL/P frequency in this cohort is 5X(3% vs 15%) higher than what is reported in families with HDGC/HLBC in literature. CDH1 P/LP variant types may impact risk of CL/P and needs further investigation. International Gastric Cancer Linkage Consortium guidelines include gastric cancer with CL/P as a criterion for genetic referral/testing, however, breast cancer with CL/P is not included. Further studies comparing cancer risks in HDGC/HLBC families with/without CL/P are needed to inform referral guidelines revisions.

PI: Kathy Calzone