PROJECT SUMMARY
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 patient-
derived 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.