Hereditary

E. Strong (ed.). Gastric cancer. Principles and practice. Springer (2015)


Approximately 10% of all gastric cancers are familial. Germline mutations in the E-cadherin CDH1 gene account for 30–40% of the rare syndrome known as hereditary diffuse gastric cancer, and gastric cancers also occur less frequently as a component of other hereditary cancer syndromes [38].

Familial diffuse gastric carcinoma

Germline mutations in CDH1 are the molecular basis for familial gastric cancer syndrome [39–42] (Fig. 4.3a). Initially identified in three Maori families in New Zealand, at least 100 families have been reported to carry the CDH1 germline mutation [43]. Given the relatively high penetrance disease (70–80%) [44], a lifetime risk of developing gastric cancer of approximately 67% in men and 83% in women [45], prophylactic total gastrectomy is often considered after a familial diagnosis of a CDH1 mutation [46]

Hereditary nonpolyposis colorectal cancer syndrome (HNPCC)

After endometrial carcinoma, gastric carcinoma is the second most common extra-colonic cancer in patients with hereditary nonpolyposis colorectal cancer (HNPCC) (Fig. 4.3b). There is a fourfold relative risk of developing gastric cancer in HNPCC patients, with the risk predominantly in younger patients (11.3-fold in the 30s and 5.5fold in the 40s). Additionally, the relative risk is greater in mutation carrier families than noncarrier families (3.2-fold versus 1.6-fold). The overall lifetime risk of developing gastric cancer is 10% for patients of Western ancestry and 30% for patients of Asian ancestry [54–57], and microsatellite instability (MSI) phenotype is noted in 65% of these cases.

Gastric cancer. Principles and practice (2015) 4.3

Fig. 4.3. Hereditary condition associated gastric neoplasms. a Early hereditary diffuse gastric carcinoma with signet ring cell morphology is present in the superficial lamina propria. b) HNPCC (Lynch syndrome) associated intestinal type gastric adenocarcinoma exhibits increased intraepithelial and stromal lymphocytes. c) An FAP associated adenocarcinoma (left) arises in a fundic gland polyp with dysplasia (upper right). d) Gastric Peutz–Jeghers polyp is composed of irregular and architecturally distorted proliferation of foveolar glands with increased inflammation in the lamina propria and smooth muscle proliferation (arrow)

Familial adenomatous polyposis coli (FAP)

Patients with familial adenomatous polyposis coli (FAP) also develop multiple gastric fundic gland polyps, which can undergo neoplastic transformation as a result of somatic mutations of the adenomatous polyposis coli (APC) gene [47] (Fig. 4.3c). However, in contrast to the development colon adenocarcinoma from adenomatous polyps in FAP patients, the development of gastric carcinoma in fundic gland polyps is rare [48–51]. Interestingly, there is a higher risk of neoplastic transformation in the stomach of Asian FAP patients as compared to Western FAP patients [52, 53].

Li–Fraumeni syndrome

Germline mutations of the TP53 gene are present in 50–70% of the patients with Li–Fraumeni syndrome.The most common neoplasms in patients with Li–Fraumeni syndrome are soft tissue sarcoma, breast cancer, and brain tumors. While gastrointestinal tract tumors account for less than 10% of all Li–Fraumeni syndrome associated neoplasms, gastric carcinomas (which may be multiple) represent more than 50% of the gastrointestinal tumors in patients with Li–Fraumeni [58, 59].

Peutz–Jeghers syndrome

Mutation of the serine/threonine–protein kinase 11 (STK11) gene, located on chromosome 19p13.3, is responsible for Peutz–Jeghers syndrome [60]. Characteristic gastrointestinal hamartomatous polyps develop (Fig. 4.3d), and these patients have an increased risk of gastric cancer, although the exact degree of risk is a subject of debate [61, 62].

Gastric hyperplastic polyposis

Gastric hyperplastic polyposis is an inherited autosomal dominant syndrome characterized by the presence of hyperplastic gastric polyposis, severe psoriasis, and an increased incidence of gastric cancer of the diffuse type [63, 64].

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