Hereditary diffuse gastric cancer: the evolution of a cancer syndrome

Hereditary Diffuse Gastric Cancer (HDGC) is a high risk cancer syndrome caused predominantly by germline mutations in the CDH1 gene. HDGC is characterised by a lifetime risk of advanced diffuse-type gastric (stomach) cancer of up to 70%, and an additional 40% lifetime risk of lobular breast cancer in women. Since the first description of HDGC in three whānau Māori in 1998, our understanding of this syndrome's life history and clinical behaviour has steadily evolved, leading to changes to its clinical management. In particular, it is now evident that the signet ring cell carcinomas that develop in the stomachs of CDH1 pathogenic variant carriers have an indolent phase, although the factors that drive progression of these early cancers to advanced disease remain to be identified. This indolent phase provides the opportunity for chemoprevention to be considered as an alternative to prophylactic surgery as a risk reduction strategy. Here, we describe the evolution of our knowledge of HDGC, with particular reference to the syndrome's penetrance, tumour spectrum and pathology.