Hereditary Diffuse Gastric Cancer: Surgery, Surveillance and Unanswered Questions

Abstract

Hereditary diffuse gastric cancer (HDGC) is an inherited cancer-susceptibility syndrome characterized by autosomal dominance and high penetrance. In 30-50% of cases, a causative germline mutation in CDH1, the E-cadherin gene, may be identified. Female carriers of CDH1 mutations also have an increased (20-40%) risk of lobular breast cancer. Endoscopic surveillance of patients with CDH1 mutations is ineffective because early foci of HDGC are typically small and underlie normal mucosa. CDH1 mutation carriers are therefore offered the option of prophylactic gastrectomy, which commonly reveals early foci of invasive signet-ring cell cancer. We review recommendations for genetic testing, surveillance and prophylactic surgery in HDGC. Areas for future research are discussed, including development of new screening modalities, optimal timing of prophylactic gastrectomy, identification of additional causative mutations in HDGC, management of patients with CDH1 missense mutations and prevention/early detection of lobular breast cancer in CDH1 mutation carriers.

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).…”

“…We also found a higher percentage of women (59%) had documented DGC compared to men (41%) (Appendix B). Patients fulfilling the modified criteria have an estimated 30-50% likelihood of harboring CDH1 mutations [8,16]. Isolated cases of DGC in young individuals from a low-incidence population have a 20% probability of harboring a CDH1 mutation [18].…”

“…Members of the Stanford Cancer Center have expanded the criteria for referral for genetic testing to include patients with pathological features strongly suggestive of HDGC (Table 1). They suggest that CDH1 testing be performed in these individuals to determine the necessity for a total rather than a subtotal gastrectomy [8,16]. The identification of CDH1 mutations in HDGC families is important to clarify the risk of DGC developing in the future for family members.…”

“…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.…”