Defining the phenotype and cancer penetrance of CTNNA1 loss-of-function germline variants

Hereditary diffuse gastric cancer syndrome (HDGC) is a hereditary condition associated with increased risk of diffuse gastric cancer and lobular breast cancer. While HDGC is classically caused by germline mutations in the CDH1 gene, recent evidence has identified the CTNNA1 gene, coding for -E-catenin, as a new putative HDGC risk gene. We previously showed that 12% and 67% of individuals with a CTNNA1 loss-of-function (LOF) variant identified on multigene panel testing had a personal history of diffuse gastric cancer or breast cancer respectively. However, given limitations of previously collected data the extent and magnitude of the cancer risks associated with LOF variants in CTNNA1 remain uncertain at this time. Elucidating accurate cancer risk estimates for CTNNA1 LOF variant carriers is critical to allow for proper cancer risk management of this affected cohort as well as their family members. Our preliminary data demonstrates that CTNNA1 LOF variant carriers can be successfully recruited as study participants, enabling collection of detailed personal and family history with creation of three-generation pedigrees that can be used for cancer penetrance analyses. Furthermore, we show that CTNNA1 LOF variant carriers may have differing variant-specific cancer risks, with potentially reduced gastric cancer risk associated with C-terminal LOF variants. Finally, we demonstrate that patient-derived gastric organoids, including from CTNNA1 LOF variant carriers, can be successfully established. Taken together we hypothesize that CTNNA1 LOF variant-specific cancer risks can be established through a combination of improved cancer penetrance estimates and patient-derived gastric organoid models. We will investigate this hypothesis by first defining the cancer penetrance of CTNNA1 LOF variant carriers through the prospective CTNNA1 Family Expansion (CAFÉ) Study, enabling collection of detailed personal and family medical history, with subsequent creation of three-generation pedigrees that will be utilized for cancer penetrance analysis. Secondly, we will determine CTNNA1 variant-specific gastric tumorigenesis using patientderived gastric organoids, which are invaluable tools for recapitulating gastric cancer development. We will utilize these patient-derived gastric organoids to test the carcinogenic potential of different CTNNA1 LOF variants. Together, the study results from this proposal will be critical for establishing variant-specific cancer risks for CTNNA1 LOF variants, which will ultimately help inform cancer risk management decisions for these affected patients and their families.