Current advances in understanding the molecular profile of hereditary diffuse gastric cancer and its clinical implications

Author:

Lim Hui JunORCID,Zhuang Lizhe,Fitzgerald Rebecca C.

Abstract

AbstractHereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome attributed to germlineCDH1mutations that carries a high risk for early onset DGC. HDGC raises a significant health issue due to its high penetrance and mortality unless diagnosed early. The definitive treatment is to undergo prophylactic total gastrectomy which is associated with significant morbidity., highlighting the urgent need for alternative treatment methods. However, there is limited literature examining potential therapeutic strategies building on emerging insights into the molecular basis of progressive lesions in the context of HDGC. The aim of this review is to summarise the current understanding of HDGC in the context ofCDH1pathogenic variants followed by a review of the proposed mechanisms for progression. In addition, we discuss the development of novel therapeutic approaches and highlight pertinent areas for further research. A literature search was therefore performed for relevant studies examiningCDH1germline variants, second-hit mechanisms ofCDH1, pathogenesis of HDGC and potential therapeutic strategies in databases, including PubMed, ScienceDirect and Scopus. Germline mutations are mostly truncatingCDH1variants affecting extracellular domains of E-cadherin, generally due to frameshift, single nucleotide variants or splice site mutations. A second somatic hit ofCDH1most commonly occurs via promoter methylation as shown in 3 studies, but studies are limited with a small sample size. The multi-focal development of indolent lesions in HDGC provide a unique opportunity to understand genetic events that drive the transition to the invasive phenotype. To date, a few signalling pathways have been shown to facilitate the progression of HDGC, including Notch and Wnt. In in-vitro studies, the ability to inhibit Notch signalling was lost in cells transfected with mutant forms of E-cadherin, and increased Notch-1 activity correlated with apoptosis resistance. Furthermore, in patient samples, overexpression of Wnt-2 was associated with cytoplasmic and nuclear β-catenin accumulation and increased metastatic potential. As loss-of-function mutations are challenging to target therapeutically, these findings pave the way towards a synthetic lethal approach inCDH1-deficient cells with some promising results in-vitro. In future, if we could better understand the molecular vulnerabilities in HDGC, there may be opportunities to offer alternative treatment pathways to avoid gastrectomy.

Funder

Medical Research Council

NIHR Cambridge Biomedical Research Centre

National Medical Research Council, Singapore

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Oncology

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