Gastric Cancer

Hereditary diffuse gastric cancer, HDGC, Familial diffuse gastric cancer

Autosomal dominant, somatic

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant susceptibility for diffuse gastric cancer, a poorly differentiated adenocarcinoma localized in the stomach wall. Gastric cancer is one of the most common cancers in the world, with the highest incidence rates in Japan (80 cases per 100,000) and eastern Asia ¹. Other areas of the world with a high incidence of stomach cancer include Eastern Europe and parts of Latin America. Incidence rates are generally lower in Western Europe and the United States (10-40:100,000) ¹. The incidence rate of diffuse-type gastric cancer in the US was reported to be ~62% ².

According to the International Gastric Cancer Linkage Consortium (IGCLC) consensus guidelines ³, clinical criteria for the genetic screening of families with suspected hereditary gastric cancer include one of the following:

• Two gastric cancer (GC) cases in a family, in which one individual developed confirmed diffuse gastric cancer (DGC) under age 50 years
• Three confirmed individuals with DGC in first- or second-degree relatives, independent of age
• A simplex case (i.e., a single occurrence in a family) of DGC occurring before age 40 years
• Personal or family history of DGC and lobular breast cancer, one diagnosed before age 50 years.

The majority of the gastric cancers occur before age 40, but the age of onset is variable both between and within families ¹. Presenting symptoms are nonspecific in the early stages of the disease. Symptoms in the late stage may include abdominal pain, nausea, vomiting, dysphagia, postprandial fullness, loss of appetite, and weight loss. Late in the course of stomach cancer, a palpable mass may be present. Tumor spread or metastasis may lead to an enlarged liver, jaundice, ascites, skin nodules, and fractures. Other cancers reported in family members include most commonly lobular breast cancer and colorectal cancer.

Gastric cancer is seen in several other cancer predisposition syndromes, including Lynch syndrome, Li-Fraumeni syndrome, familial adenomatous polyposis, Peutz-Jeghers syndrome and Cowden syndrome.

Lynch syndrome, which is associated with germline pathogenic variants in mismatch repair genes, predisposes heterozygotes to colorectal and other cancers. Gastric cancer is the third most common cancer in these individuals. IGC is the predominant subtype in Lynch syndrome ⁴.

Microsatellite instability (MSI) was observed in approximately 15% of gastric cancers from individuals in Florence, Italy, an area with high gastric cancer risk ⁵. Gastric cancers with high MSI tend to occur in the antrum of the stomach, be of the intestinal type, and offer better survival rates.

Familial adenomatous polyposis (FAP) is caused by germline pathogenic variants in APC. Gastric cancer has been seen in 0.6% of persons with FAP ⁶.

Cancers associated with Li-Fraumeni syndrome are caused by pathogenic variants in either TP53 or CHEK2. Both DGC and IGC are observed ⁷.

An increased risk of gastric cancer has been associated with pathogenic variants in BRCA1 and BRCA2 ^{8, 9}. Gastric cancer occurs in 5.7% of families with the BRCA2 6174delT pathogenic variant ¹⁰. In a subset (7%) of individuals with gastric cancer, a BRCA2 pathogenic variant may be the underlying genetic cause ¹¹.

Hereditary diffuse gastric cancer is caused by a heterozygous germline variant in the E-cadherin gene (CDH1) on chromosome 16q22. A somatic variant in the CDH1 gene has also been found in patients with sporadic diffuse gastric cancer and lobular breast cancer. In addition to CDH1, several other genes have been associated with gastric cancer: BMPR1A, CDH1, EPCAM, MLH1, MSH2, MSH6, PMS1, PMS2, SMAD4 (table).

With genetic testing, we are able today to providedetect detection of genetic gastric cancer susceptibility (for instance. HDGC) in order to prevent cancer development in affected patients and thereby reduce cancer mortality. Genetic testing for gastric cancer is also the most accurate means of determining the risk of hereditary gastric cancer.

Treatment of gastric cancer includes different approaches, such as surgery, chemotherapy, radiotherapy, and targeted therapy. 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 gastrectomy. Care by a multidisciplinary team comprising specialists with expertise in clinical 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.

CENTOGENE experts have designed the Gastric cancer panel which includes these genes: BMPR1A, CDH1, EPCAM, MLH1, MSH2, MSH6, PMS1, PMS2, SMAD4.

The differential diagnosis of gastric cancer-related disorders – depending on the major symptoms in the initial case – includes the following diseases¹:

• Lynch syndrome, caused by pathogenic variant in one of the mismatch repair genes
• Familial adenomatous polyposis (FAP), caused by germline pathogenic variants in APC gene
• Li-Fraumeni syndrome, caused by pathogenic variants in either TP53 or CHEK2 genes
• BRCA1 and BRCA2 hereditary breast and ovarian cancer
• Carney complex, caused by pathogenic variants in PRKAR1A gene
• Carney-Stratakis syndrome, caused by pathogenic variants in SDHB, SDHC, and SDHD genes.

CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for ovarian cancer using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no pathogenic variant is identified after analysis of the Gastric cancer panel, we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.

Genetic testing for gastric cancer is recommended for persons who show one or more of the following features:

• History of colon or any gastrointestinal cancer
• Positive family history of gastric cancer and premalignant gastrointestinal conditions
• Present gastrointestinal conditions and a family history of cancer
• History of chronic and complex gastrointestinal condition.

   

Sequencing, deletion/duplication of gastric cancer related genes should be performed in all individuals suspected of having gastric cancer. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of variants, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of gastric cancer, identify at-risk family members, provide information about reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.