Globally, hereditary diffuse gastric cancer (HDGC) accounts for less than 3% of gastric cancers. HDGC is an autosomal dominant syndrome caused by mutations in the CDH1 or CTNNA1 genes. For patients with a CDH1 mutation, the cumulative risk at age 80 for diffuse gastric cancer is 70% for men and 56% for women; however, the age of onset varies from age 14 to 85. Annual endoscopic surveillance is recommended for patients younger than 20. However, prophylactic gastrectomy between ages 20 to 30 is recommended for patients with pathogenic CDH1 mutations.
Familial intestinal gastric cancer is an autosomal dominant syndrome, but an underlying genetic mutation has not yet been identified. Currently, there is no specific recommendation for patients at risk of this syndrome, other than eradication of Helicobacter pylori, if present.
Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is considered to be a variant of FAP with a predominant gastric phenotype because it is caused by point mutations in the 1B promoter of the APC gene. The age of onset is between 23 and 75. ESMO recommends surveillance by endoscopy with random biopsies and polypectomies of larger or irregular polyps. Individualized management is required and some patients may benefit from a prophylactic gastrectomy.
Hereditary pancreatic cancer accounts for approximately 10% of all pancreatic cancer cases. Of these cases, 10% to 15% are associated with hereditary syndromes such hereditary breast/ovarian cancer, familial atypical multiple mole melanoma, Lynch syndrome, FAP, ataxia telangiectasia, Peutz-Jeghers syndrome, and hereditary pancreatitis. BRCA2 mutations are the most common cause of hereditary pancreatic cancer, but in most cases, a genetic mutation is not identified, which is called familiar pancreatic cancer (FPC). Within these families, some studies have reported mutations in BRCA1, BRCA2, PALB2, or CDKN2A genes. Therefore, the ESMO guideline recommends that multigene panel testing be performed for families with a history of FPC to identify any potential underlying genetic mutation.
Surveillance of pancreatic cancer is recommended for high risk individuals. High risk is defined as (1) patients with 3 or more blood relatives with pancreatic cancer, one of whom must be a first-descendent relative; (2) patients with at least 2 first-descendent relatives with pancreatic cancer; (3) patients who harbor a mutation in CDKN2A, BRCA2, PALB2, or with Lynch syndrome and a first-descendent relative with pancreatic cancer; or (4) patients with Peutz-Jeghers syndrome. Surveillance is performed by annual endoscopic ultrasound or pancreatic MRI beginning at age 50, or 10 years earlier than the youngest affected family member. However, surveillance should begin at age 30 for patients with Peutz-Jeghers syndrome and age 40 for those with hereditary pancreatitis. If a suspicious lesion is detected, ESMO recommends a multidisciplinary team to determine optimal treatment based on an individualized assessment.
- Stjepanovic N, Moreira L, Carneiro F, et al. Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up [published online August 5, 2019]. Ann Oncol. doi:10.1093/annonc/mdz233