Large cohort analysis of incidental CDH1 PVs among patients undergoing MGPT.

10618 Background: Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant condition caused by a heterozygous pathogenic variant (PV) in CDH1.HDGC is associated with an increased risk for DGC (33-70%) and invasive lobular breast cancer (LBC) (~64%) 1. The National Cancer Center Network (NCCN) and International Gastric Cancer Linkage Consortium (IGCLC) recommend consideration of CDH1 germline testing based on personal and family history of DGC and LBC. However, with the advent of next generation sequencing and the inclusion of CDH1 in multigene panels (MGP), several cohort studies have identified CDH1+ patients who do not meet criteria 2,3,4,5. Our group previously analyzed a cohort of patients with a personal or family history of BC who had CDH1 testing through MGPT and did not observe a significant association between CDH1 PVs and suspicion for HDGC (p-value=0.2066) 6. In this expanded study, we aim to evaluate a larger cohort of patients of all cancer histories to gain a more comprehensive picture of the prevalence of incidental CDH1 PV among patients undergoing MGPT. Methods: 14,891 individuals who underwent CDH1 testing within MGPT were seen at MD Anderson’s Clinical Cancer Genetics (CCG) program between August 2013 and January 2024. This cohort was obtained from a prospectively maintained patient database within MD Anderson’s CCG program. Individuals were stratified based on CDH1 germline status (PV vs. negative or variant of uncertain significance) and meeting modified criteria for HDGC. Results: Within our expanded cohort, 1,716 individuals (11.5%) met criteria for suspicion for HDGC, while 13,715 did not meet criteria. Of the 70 individuals who tested positive for CDH1 (0.47%), 39 (0.28%) met criteria while 31 (0.23%) did not. We observed a statistically significant relationship between meeting our modified criteria for suspicion for HDGC and testing positive for a pathogenic variant in CDH1 (p-value <0.0001). Conclusions: Among patients who underwent CDH1 testing within MGPT, we observed a correlationbetween having a CDH1PV and meeting criteria for suspicion for HDGC. This contrasts with prior findings from our breast cancer cohort, potentially due to the limited number of CDH1 positive patients (n=3). These results suggest that while perhaps not robustly capturing HDGC families within a sub-population of patients undergoing MGPT, overall, NCCN and IGCLC guidelines closely reflect the clinical picture of a significant number of HDGC families. Meanwhile, the presence of incidental CDH1 PVs in this cohort portrays the variable expressivity and incomplete penetrance among patients with HDGC, including the detection of occult signet ring cell carcinomas during endoscopies or total gastrectomies 7. We seek to expand this analysis by comparing these findings to rates of incidental CDH1 PVs in a subset of patients who meet NCCN guidelines for CDH1 testing based on suspicion for hereditary breast cancer syndromes.