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Gastric cancer is one of the most commonly diagnosed cancers in the world, with an incidence of over 1 million cases and an estimated 769,000 deaths occurring in 2020. Globally, this cancer ranked fifth for cancer incidence and fourth for cancer mortality in 2020.[
The genes that can predispose individuals to hereditary diffuse gastric cancer (HDGC) include the following:
HDGC is the most common hereditary cancer syndrome that can predispose individuals to gastric cancer. This disease does not have an easily detectable precursor lesion. For more information, see
There are also hereditary cancer syndromes that can cause other forms of gastric cancer. These syndromes include the following:
In each of these syndromes, gastric polyps and gastric cancer risk are of secondary importance to colorectal polyps and colorectal cancer. Gastric polyp burden (including polyp count and size) and gastric cancer risk may vary between individuals.
For more information on these genetic syndromes, see
Gastric Cancer Risk Factors
Environmental risk factors
Incidence rates for gastric cancer are the highest in Eastern Asia and Eastern Europe, while the rates in Northern America, Northern Europe, and Africa are generally low.[
Environmental risk factors for gastric cancer include the following:
1. Helicobacter pylori (H. pylori) infection.
2. Diet.
3. Migrant effects.
4. Tobacco use.[
5. Alcohol use.[
6. Emerging evidence for obesity and gastroesophageal reflux disease (GERD).
7. Racial and ethnic disparities.
Intensive surveillance may be clinically warranted in individuals with hereditary, environmental, or ethnicity-based gastric cancer risk factors. However, more data are needed to show whether these risk factors increase or decrease gastric cancer risk in individuals with hereditary gastric cancer pathogenic variants. For more information about risk factors for gastric cancer in the general population, see
Familial risk factors
Individuals with family histories of gastric cancer have an increased risk of developing gastric cancer.[
Families with multiple gastric cancer cases have also been used to study the heritability of gastric cancer. A report in 1964 described a large, native Maori family from New Zealand.[
Precancerous Lesions
In the stomach, gastric adenocarcinoma can arise from visible lesions, from the histological progression of mucosal atrophy or, less commonly, from invisible lesions (i.e., submucosal infiltration, as seen in diffuse-type gastric adenocarcinoma). This section reviews both gastric polyps and the histological changes associated with chronic gastritis that can predispose an individual to gastric cancer.
Gastric polyps
Gastric polyps are common in the U.S. population and are found in up to 6% of individuals who undergo endoscopy. However, these polyps rarely progress to become gastric cancer.[
In general, the malignant potential of a polyp is determined by the polyp's histology, size, and degree of dysplasia, if present. Adenomatous and hyperplastic polyps have the highest malignant potentials, especially when H. pylori is present. In contrast, fundic gland polyps (with or without dysplasia) rarely progress to become gastric cancer, even in individuals who have FAP.[
Fundic gland polyps of the stomach are common and typically associated with long-term proton pump inhibitor (PPI) use.[
Inflammatory and hyperplastic polyps can present with many different pathological features. Unlike the colon, in which hyperplastic polyps carry little or no cancer risk, hyperplastic polyps of the stomach can enlarge and develop dysplastic foci.[
Hamartomatous polyps are seen in the stomachs of patients with PJS, JPS, and PHTS. For more information on these hereditary cancer syndromes, see
Gastric adenomas make up approximately 10% of all gastric polyps. A gastric adenoma's malignant potential is determined by its histological subtype and size.[
Chronic gastritis
Chronic gastritis, a histological diagnosis defined by the presence of a mononuclear cellular infiltrate in the lamina propria of the stomach, occurs due to environmental exposures or autoimmune gastritis. Chronic gastritis can lead to gastric intestinal metaplasia. H. pylori is the most common risk factor for intestinal metaplasia. Other risk factors for intestinal metaplasia include pernicious anemia, autoimmune gastritis, ethnicity, a family history of gastric cancer, dietary habits, smoking, and alcohol use.[
The steps of Correa's cascade include the following:
Although these histological changes are associated with increased gastric cancer risk in the general population, the prevalence of findings and associated cancer risk in hereditary cancer syndromes is unknown. Each step in Correa's cascade only occurs in a minority of patients. There is considerable controversy regarding appropriate surveillance in patients with intestinal metaplasia.[
Endoscopic assessment
Gastric cancer screening is not routinely performed in the United States, where gastric cancer incidence is relatively low. Gastric cancer screening is also not usually performed in individuals with family histories of gastric cancer in which a hereditary gastric cancer pathogenic variant has not been identified. Large, prospective multicenter studies are needed to determine if gastric cancer screening programs would improve mortality in individuals from the United States with family histories of gastric cancer. In the United States, gastric cancer surveillance guidelines only exist for individuals with pathogenic variants in CDH1 or other gastric cancer risk genes (for more information, see
When evaluating any patient with hereditary gastric cancer risk, endoscopy includes assessment for gastric polyps and H. pylori —despite a lack of evidence demonstrating that H. pylori increases gastric cancer risk in the setting of all hereditary cancer syndromes.[
A small focus of intestinal metaplasia in the antrum is shown below. Intestinal metaplasia is not always visible on endoscopy. Instead, it is often found when taking random biopsies of the stomach.[
Endoscopic image showing a small area of intestinal metaplasia (circled in yellow) in the antrum of the stomach.
References:
Approximately 15% to 20% of gastric cancers may be caused by hereditary gastric cancer syndromes.[
The following items are important to elicit when collecting a patient's family history:
a It is recommended that family history analysis focus on gastric cancer and other cancers (such as lobular breast cancer) that may be associated with hereditary diffuse gastric cancer (HDGC).
For information on collecting a family history, see the
In busy clinical settings, it might not be feasible to obtain a complete family history.[
Many factors can contribute to inaccurate reporting of a gastric cancer family history. In medicine, the stomach has a distinct definition and anatomical location in the body. The public's definition of the stomach is more ambiguous, which could lead to reporting inaccuracies.[
The poor validity of self-reported gastric cancer family histories needs to be considered during a patient's genetic evaluation and when creating an individual's clinical management recommendations. Studies have assessed the accuracy of self-reported family histories by comparing collected information with confirmation sources like death certificates, cancer registries, and histopathological records.[
Obtaining pathological documentation of personal/family histories of cancer and polyps is also integral when assessing a patient's hereditary gastric cancer risk. This documentation is especially important because genetic testing criteria has shifted over the years and has, in turn, broadened clinical criteria.[
The diagnosis of cancers before age 50 years is a hallmark feature of hereditary cancer syndromes. Attenuated forms of hereditary cancer syndromes also exist and are increasingly recognized. In these attenuated syndromes, the ages of gastric cancer onset can occur after age 50 years.[
Genetic Testing Approach
Patients who develop gastric cancer usually present at an advanced stage.[
Germline genetic testing criteria exists for the following genes associated with gastric cancer and/or gastric polyps: CDH1, CTNNA1, APC, STK11, SMAD4, and the Lynch syndrome genes (MLH1, MSH2, MSH6, EPCAM).[
When the patient has multiple cancers in the family that overlap with more than one hereditary cancer syndrome, another option is ordering multigene panel testing for all suspected genes. Multigene panel testing is the simultaneous testing of many genes for pathogenic and likely pathogenic variants, often at costs comparable to single-gene genetic testing. Hereditary cancer multigene panel testing includes cancer site-specific panels, high- or moderate-risk gene panels, guideline-based panels, and pancancer panels.[
For more information about selecting the appropriate genetic test, see the
Multigene panel testing implications
This section briefly summarizes the implications for patients undergoing multigene panel testing for hereditary gastric cancer syndromes. For more information about multigene panel testing, including genetic education, counseling considerations, and research, see the
Multigene panel testing can present challenges, including the unexpected discovery of pathogenic variants in genes that would not have been considered based on the patient's personal and/or family history. Pathogenic variants in many hereditary cancer genes can increase an individual's risk of developing more than one type of cancer. For instance, CDH1 pathogenic variants are associated with increased risk for both diffuse gastric cancer and lobular breast cancer.[
Cascade genetic testing
Cascade genetic testing identifies relatives who are at risk for a genetic condition by following the logical path of a pathogenic variant in a family. Cascade genetic testing is routinely offered to at-risk relatives once a pathogenic variant is identified. For more information, see the
References:
The major heritable syndromes associated with increased gastric cancer risk are listed in
Syndromea | Gene | Gastric Cancer Risk | Gastric Cancer Pathology | Gastric CancerSurveillance | Other Characteristics |
---|---|---|---|---|---|
CNS = central nervous system; CRC = colorectal cancer; EGD = esophagogastroduodenoscopy; GI = gastrointestinal; GIST = gastrointestinal stromal tumor. | |||||
a All conditions are inherited in anautosomal dominantfashion, unless otherwise specified. | |||||
b High-risk lesions include tubular adenomas, polyps with high-grade dysplasia, and pyloric gland adenomas. | |||||
c Prophylactic total gastrectomy is not recommended prior to age 40 y. However, it may be considered for certain patients, especially those with a family histories of gastric cancer prior to age 25 y. | |||||
|
CDH1andCTNNA1 | 33%–83%[ |
Diffuse type, signet ring cell carcinoma | EGD with multiple random biopsies of the stomach every 6–12 moor risk-reducing total gastrectomy between ages 18–40 yc[ |
For CDH1 only: Lobular breast cancer, cleft lip or cleft palate. It is currently unknown whetherCTNNA1is associated with lobular breast cancer or cleft lip or cleft palate |
|
APC | 1.3%–5% in FAP and AFAP.[ |
Intestinal type | EGD for duodenal surveillance is also adequate surveillance for gastric cancers. Gastrectomy can be considered for patients with high-risk lesions that cannot be managed endoscopicallyb[ |
Gastric polyps (fundic gland polyps and adenomas), CRC, colorectal polyps (adenomas), desmoid tumors, duodenal tumors and cancer, thyroid cancer, brain cancer, ampullary cancer, pancreatic cancer, hepatoblastoma |
|
APC | ||||
|
APC(pathogenic variants/single nucleotide variantin the promoter 1B region ofAPCare associated with GAPPS-7) | In GAPPS, gastric cancer risk is significantly increased, but exact risk numbers are unknown[ |
|||
|
MLH1,MSH2,MSH6,PMS2,EPCAM | 0.2%–9% | Intestinal type | Upper GI surveillance with EGD (preferably performed in conjunction with colonoscopy) starting at age 30–40 y (or earlier based on the patient's family history). Repeat EGD every 2–4 y[ |
CRC, endometrial cancer, ovarian cancer, breast cancer, pancreatic cancer, bladder cancer, biliary tract cancer, urothelial cancer, small bowel cancer, prostate cancer, brain/CNS tumor |
|
STK11(also known asLKB1) | 29%[ |
Intestinal type (arising from dysplasia in hamartomas) | EGD every 2–3 y beginning in the late adolescence[ |
Hamartomatous GI polyps; breast cancer; CRC; small bowel cancer; pancreatic cancer; Sertoli cell tumors of the ovary and testes; cervical adenoma malignum; endometrial cancer; lung cancer; mucocutaneous hyperpigmentation of the mouth, lips, nose, eyes, genitalia and/or fingers |
|
SMAD4,BMPR1A | 21% if multiple polyps are present | Intestinal type (arising from dysplasia in juvenile polyps/hamartomas) | EGD every 2–3 y. If polyps are found, conduct EGD at shorter intervals based on polyp size, number, and pathology[ |
Juvenile/hamartomatous colorectal polyps, CRC, hereditary hemorrhagic telangiectasia |
|
TP53 | 2.8% | Possibly intestinal type | Breast cancer, adrenocortical carcinoma, sarcoma, brain/CNS tumor, leukemia |
References:
Preliminary evidence has linked gastric cancer to other genes that are not typically associated with this type of cancer, such as ATM, BRCA1, BRCA2, BRIP1, PALB2, and RAD51D. Studies suggest a possible association between gastric cancer risk and pathogenic variants in both established gastric cancer genes and in moderate- and high-risk genes that are not typically associated with gastric cancer. However, clinical practice changes are not indicated based on this preliminary evidence.
Several studies searched for candidate genes in hereditary gastric cancer cases that were not associated with CDH1 pathogenic variants. Some of these cases may be explained by pathogenic variants in homologous recombination (HR) DNA repair genes, particularly PALB2:
In summary, these findings suggest that defects in HR genes increase risk for gastric cancer and highlight a role for the known cancer predisposition gene, PALB2 as a potential candidate gene for hereditary gastric cancer. However, case-control studies are needed to confirm whether PALB2 is associated with hereditary gastric cancer susceptibility. Gastric cancer screening is not indicated for PALB2 carriers.
Additional studies investigated potential candidate genes for gastric cancer:
Additional studies are warranted to determine if there is a causal relationship between these genes and gastric cancer risk. However, the rate of pathogenic variants found in these studies supports the use of multigene panels in patients with gastric cancer undergoing germline genetic testing. For more information, see the
References:
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