Genetics of Hereditary Diffuse Gastric Cancer: Progress and Future Challenges

Abstract

Hereditary diffuse gastric cancer (HDGC) is a rare cancer susceptibility syndrome. One third of HDGC syndrome families carry germline mutations of the E-cadherin gene. Owing to the limitation of the current endoscopic screening techniques and since no chemoprevention is yet available, total prophylactic gastrectomy is the only option offered to carriers of inactivating mutations in genetic counseling. In this regard, 30% of the E-cadherin germline mutations reported to date are of the missense type, and since their pathogenic significance is not straightforward, the management of carriers of such mutations is suboptimal. In the absence of definitive clinical evidence, functional in vitro studies together with in silico analysis have been used to infer the pathogenic significance of germline missense mutations. Since most of the HDGC families reported to date are negative for E-cadherin germline mutations, the identification of alternative genes underlying the tumorigenesis of diffuse gastric has become an important target for research.

A systematic review of the indications for genetic testing and prophylactic gastrectomy among patients with hereditary diffuse gastric cancer

“…Additionally, the prevalence of mutations in patients without a family history of GC was unknown; thus, the IGCLC believed it was premature to offer genetic testing for sporadic cases [3]. Since then, the prevalence of CDH1 mutations in families with a history of lobular breast cancer and/or colon cancer, as well as the prevalence of CDH1 mutations among young individuals with GC and no family history of the disease from low-incidence populations, has been documented and the criteria for CDH1 testing have been modified [5,7,8,11,[15][16][17][18] (Table 1). We found that patients with a family history of GC (histology unknown) and documented DGC who tested positive for CDH1 mutations also had a family history of breast cancer and/or colon cancer ( Table 2).…”

“…A negative test result does not mean the patient will not develop GC [3]. These patients should still be followed up with gastric screening similar to that done in at-risk families, as it is possible a mutation exists in the CDH1 gene that has not yet been discovered [7]. Currently, all patients who have undergone a prophylactic gastrectomy despite a negative test result (or prior to determining the results of CDH1 screening) have been deemed negative for cancer upon histological examination (Fig.…”

“…After removal of duplicates and screening for relevant titles and abstracts, a total of 96 articles were submitted for a full-text review. A total of 70 articles [3,[5][6][7][8] met our inclusion criteria and were included in this review (Fig. 1).…”

“…HDGC is an autosomal dominant cancer syndrome caused by germline mutations to the CDH1 gene that encodes for the cell-to-cell adhesion protein E-cadherin [6][7][8]. Genetic linkage between CDH1 mutations and HDGC was first described by Guilford et al [9,10], who identified germline truncating E-cadherin mutations in three New Zealand Maori families in 1998.…”

“…A paradox is noted for Asian countries, where a high incidence of sporadic GC is present, but a low incidence of CDH1 mutations has been found. The reason for this is unknown [2,5,7].…”