Hereditary diffuse gastric cancer (HDGC) is an inherited cancer susceptibility syndrome characterized by an elevated risk for diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Some patients fulfilling the clinical testing criteria harbor a pathogenic CDH1 or CTNNA1 germline variant. However, the underlying mechanism for around 80% of the patients with a family or personal history of DGC and LBC has so far not been elucidated. In this cohort study, patients meeting the 2015 HDGC clinical testing criteria were included, and subsequently, CDH1 sequencing was performed. Of the 207 patients (161 families) in this study, we detected 21 pathogenic or likely pathogenic CDH1 variants (PV) in 60 patients (28 families) and one CTNNA1 PV in two patients from one family. Sixty-eight percent (n = 141) of patients were female. The overall PV detection rate was 18% (29/161 families). Criterion 1 and 3 of the 2015 HDGC testing criteria yielded the highest detection rate of CDH1/CTNNA1 PVs (21% and 28%). PV carriers and patients without proven PV were compared. Risk of gastric cancer (GC) (38/62 61% vs. 102/140 73%) and age at diagnosis (40 ± 13 years vs. 44 ± 12 years) were similar between the two groups. However, GC was more advanced in gastrectomy specimens of patients without PV (81% vs. 26%). LBC prevalence in female carriers of a PV was 20% (n = 8/40). Clinical phenotypes differed strongly between families with the same PV. Emphasis should be on detecting more causative genes predisposing for HDGC and improve the management of patients without a proven pathogenic germline variant.

Lynch syndrome is an autosomal dominant cancer predisposition syndrome and the most common cause of hereditary colorectal cancer. In addition to colorectal cancer, it confers substantially increased risks for several extracolonic malignancies. While there is broad consensus regarding the effectiveness of endoscopic colorectal surveillance, recommendations for surveillance of gastric, small bowel, and pancreatic cancers vary considerably among guidelines issued by leading professional societies. These discrepancies largely reflect the limited availability of robust, high-quality evidence. In this narrative review, we summarize the cancer risks for gastric, small bowel, and pancreatic malignancies in Lynch syndrome carriers, discuss recent studies evaluating the outcomes of surveillance strategies, and provide an overview of current guideline recommendations. Furthermore, we highlight emerging approaches that may enhance surveillance strategies in the future. In recent years, increasing research efforts have focused on surveillance for less frequent Lynch syndrome-associated malignancies, however, prospective data from large, well-characterized cohorts remain scarce. Such data are essential to harmonize existing guidelines and to enable the development of personalized surveillance strategies for individuals affected by Lynch syndrome.