Hereditary Diffuse Gastric Cancer in a Japanese Family with CDH1 Mutation: Three Individuals Undergoing Total Gastrectomy Following Presymptomatic Genomic Diagnosis

Abstract

Abstract Background; Germline pathogenic variants in the E-cadherin gene CDH1 cause hereditary diffuse gastric cancer (HDGC), which is an autosomal dominant cancer syndrome, accounting for 1% of all gastric cancers. HDGC harboring a CDH 1 variant is extremely rare in Japan. Method; Here, we describe four cases of HDGC in a single Japanese family. Results; The proband exhibited advanced and metastatic gastric cancer, and was found to have a previously reported heterozygous frameshift variant in CDH1 (NM_004360.3:c.1009_1010del:p.Ser337Phefs*12). Five at-risk relatives underwent presymptomatic molecular testing after careful genetic counseling, and three were molecularly diagnosed as positive for the variant. Esophagogastroduodenoscopy was performed in three relatives, which revealed abnormal small pale mucosal patches, small ulcerative lesion, and no abnormal findings, respectively. Random and targeted biopsies were compatible with the pathological diagnosis of HDGC. They underwent total gastrectomy and Roux-en-Y reconstruction with D2 lymph node dissection. Conclusion; In the management of HDGC, multidisciplinary and family-oriented approaches are critical, including genetic analysis of CDH1 variants in the proband, presymptomatic diagnosis of at-risk relatives through careful genetic counseling, and random biopsy-based surgery or prophylactic total gastrectomy.