Hereditary Diffuse Gastric Cancer

Excerpt

Clinical characteristics: Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant susceptibility for diffuse gastric cancer, a poorly differentiated adenocarcinoma that infiltrates into the stomach wall causing thickening of the wall (linitis plastica) without forming a distinct mass. Diffuse gastric cancer is also referred to as signet ring carcinoma or isolated cell-type carcinoma. The average age of onset of HDGC is 38 years (range: 14-69 years). The majority of the cancers in individuals with a CDH1 pathogenic variant occur before age 40 years. The estimated cumulative risk of gastric cancer by age 80 years is 70% for men and 56% for women. Women are also at a 42% risk for lobular breast cancer.

Diagnosis/testing: A diagnosis of HDGC is established in a proband with:

1. Diffuse gastric cancer (DGC) and a family history of one or more first- or second-degree relatives with GC; OR

2. A personal and/or family history of DGC diagnosed before age 40 years; OR

3. A personal and/or family history of DGC and LBC, one diagnosed before age 50 years.

If clinical features and family history are inconclusive, identification of a heterozygous germline CDH1 pathogenic variant by molecular genetic testing confirms the diagnosis and allows for family studies.

Management: Treatment of manifestations: Ideally, management of individuals who have a CDH1 cancer-predisposing variant is either intense surveillance for early detection and treatment of gastric cancer or prophylactic total gastrectomy. Care by a multidisciplinary team comprising those with expertise in medical genetics, gastric surgery, gastroenterology, pathology, and nutrition is recommended. For women, referral to a high-risk breast cancer clinic is recommended; prophylactic mastectomy may be considered.

Surveillance: To date, the optimal management of individuals at risk for a cancer-predisposing variant has been controversial because of the unproven value of surveillance regimes and the potential morbidity and mortality from prophylactic gastrectomy.

Pregnancy management: Women who have undergone prophylactic total gastrectomy (PTG) and are pregnant should be followed closely by their physician and a dietician who is aware of the situation.

Genetic counseling: Hereditary diffuse gastric cancer is inherited in an autosomal dominant manner. The vast majority of individuals with a pathogenic variant predisposing to diffuse gastric cancer have inherited it from one parent. De novo pathogenic variants have been reported. Each child of a proband has a 50% risk of inheriting the cancer-predisposing variant. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in the family is known; however, requests for prenatal testing for conditions that (like HDGC) do not affect intellect and have some treatment available are not common.