Second-hit <i>CDH1</i> gene mechanisms in hereditary diffuse gastric and lobular breast cancer syndrome: frequency and impact on tumorigenesis

Hereditary diffuse gastric and lobular breast cancer (HDGLBC) is an inherited cancer syndrome predominantly characterized by diffuse gastric cancer (DGC) and lobular breast cancer (LBC). LBC often serves as the initial manifestation of HDGLBC, even in the absence of DGC symptoms. Despite advancements in medical technology and treatment, gastric cancer remains a major health burden globally. Approximately 1%-3% of gastric cancers are attributed to hereditary cancer syndromes, with pathogenic variants in the CDH1 gene being a significant contributor. CDH1 encodes E-cadherin, a protein essential for cell-cell adhesion in epithelial tissues. CDH1 inactivation through germline mutations leads to a high risk of developing DGC and LBC. The inactivation process involves a 'second hit' mechanism, commonly promoter methylation, leading to the loss of E-cadherin expression and subsequent tumorigenesis. Additionally, mechanisms such as loss of heterozygosity and somatic mutations contribute to CDH1 inactivation. Current research highlights the complexity of these mechanisms and their role in HDGLBC pathogenesis. Therapeutic strategies targeting these pathways, including epigenetic drugs and synthetic lethal approaches, show promise in restoring CDH1 function and inhibiting tumor progression. Given the aggressive nature of HDGLBC, early diagnosis and personalized treatment plans are crucial. Surveillance for LBC in CDH1 mutation carriers should be prioritized, considering prophylactic mastectomy and chemoprevention. This narrative review highlights the need for understanding the genetic and epigenetic alterations in HDGLBC, which provide critical insights for developing effective therapies and improving patient outcomes. Further research is necessary to refine these strategies and explore novel therapeutic targets.