Hereditary Diffuse Gastric Cancer: A Comparative Cohort Study According to Pathogenic Variant Status

SIMPLE SUMMARY: Pathogenic germline variants in CDH1 and CTNNA1 lead to a high prevalence of diffuse gastric cancer and breast cancer in carrier families. However, in most families with hereditary diffuse gastric cancer syndrome, the underlying genetic alteration remains elusive. In this cohort study we report on patients who met the criteria for genetic testing and compare carriers of a pathogenic CDH1/CTNNA1 variant with patients without diagnosis of a pathogenic germline variant. Gastric cancer prevalence in both groups was high and patients were diagnosed at an early age. Prevalence of breast cancer in female patients with a confirmed pathogenic variant (CDH1) was lower than previously described. Given the early age of onset in families with a suspected hereditary etiology of gastric cancer, further research is required aimed at improving clinical management and potentially the outcome in these patients. ABSTRACT: 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.