Hereditary diffuse gastric cancer: diagnosis, genetic counseling, and prophylactic total gastrectomy

Abstract

Background: A subset of patients with diffuse gastric cancer harbor deleterious cancer-causing germline mutations in the type 1 E-cadherin (epithelial) gene (CDH1), which predisposes to the autosomal dominantly inherited hereditary diffuse gastric cancer (HDGC) syndrome. These mutations are associated with a 70% life-time risk for diffuse gastric cancer (DGC) and an additional 40% risk for lobular breast cancer in women. Management options for unaffected mutation carriers include prophylactic total gastrectomy.

Methods: Four HDGC pedigrees from a cohort of 56 CDH1 mutation-positive families were subjected to further analysis. Cancer diagnoses, whenever possible, were verified with pathology reports and/or slides/tissue block review. Genetic counseling for family members covered the natural history of HDGC, the pros and cons of mutation testing, the lack of effective screening procedures available to CDH1 mutation-positive individuals, and the option for them of prophylactic total gastrectomy.

Results: Within the 4 families, carrier testing for mutations in the CDH1 gene was carried out on 52 individuals, including 25 individuals who were positive for mutation. Prophylactic gastrectomies were performed on a total of 17 individuals from 3 of the families, including 11 first cousins from 1 of the families. Occult DGC was diagnosed in gastrectomy specimens from 13 of 17 individuals (76.5%). During follow-up questioning, each of the 11 cousins stated that the decision for the prophylactic procedure was the "right one" for them.

Conclusions: Unaffected mutation carriers from HDGC families face difficult decisions and can be assisted best through education and interactions with counseling by an informed multidisciplinary team.

Figure 1

This hereditary diffuse gastric cancer (HDGC) family features 11 first cousins who underwent prophylactic total gastrectomy, 10 of whom manifested submucosal signet cell cancer at the time of surgery. All of these individuals agreed that this preventive surgery was appropriate. Particularly, they noted parents who had died of diffuse gastric cancer (DGC).

Figure 2

This pedigree depicts an HDGC family wherein 3 of the proband’s siblings died of DGC within an 18-month time period. The findings of CDH1 mutation in the 78-year-old mother (II-2) of the sibship and in her sister (II-7) at age 80, both symptom free, indicated reduced penetrance of this mutation.

Figure 3

This is an HDGC pedigree which was initially thought to be a hereditary breast-ovarian cancer (HBOC) syndrome family with a BRCA1 or BRCA2 mutation, since the proband (III-1) had bilateral breast cancer and ultimately died of DGC. Importantly, her mother (II-5) also had breast cancer and her maternal grandmother (I-5) had ovarian cancer. Mutational testing identified the CDH1 germline mutation.

Figure 4

This is an HDGC family wherein initial testing was done on III-6, found to be positive for a CDH1 mutation. She was selected because through two marriages she had sons (IV-5, IV-6) with DGC, and her mother (II-2) died of gastric cancer. Thus, III-6 was considered an obligate germline mutation carrier, which was confirmed by the presence of the deleterious CDH1 mutation.