Genes and Stomach Cancer

Presentation by:

Melyssa Aronson, MS, (C)CGC
Senior Genetic Counsellor
Zane Cohen Centre, Mount Sinai Hospital
Presented on: November 14, 2016

Presentation Summary
Please click the image below to view the original PowerPoint presentation

Take Home messages:

Most stomach cancer is sporadic (non-hereditary)
Children under the age of 18 years cannot be genetically tested
Red Flags for hereditary syndromes include early‐onset of cancer, multiple related cancer types in one person, multiple relatives affected by cancer over multiple generations
Patients with these red flags are the ones that should speak to a doctor about genetic testing
The TYPE of stomach cancer (diffuse vs intestinal type) impacts how genetic testing is done
The most common stomach cancer syndrome is Hereditary Diffuse Gastric Cancer (HDGC) and its is caused by a mutation in the CDH-1 gene
Other syndromes can explain diffuse and intestinal type of stomach cancer
The majority of families that appear high‐risk for hereditary cancer have no stomach cancer gene identified
Genes linked to stomach cancer are continuously being discovered, so if you tested negative for hereditary form of stomach cancer but suspect a genetic cause, consider being re-tested in the future

Types of Stomach Cancer

90-95% Adenocarcinoma: cancer that arises from the gastric epithelium (stomach lining)
4% Lymphoma: cancer that arises from the lymphatic system
3% Cacinoid: neuroendocrine tumors that can arise in several places
2% Sarcoma (GIST): cancer that arises from connective tissue
2% other: metastasis, cancer in the esophagus or gastroesophageal (GE) junction

Adenocarcinomas can be further subdivided into:
1) Intestinal-Type: most common type, accounts for 54% cases. Usually an end result of chronic inflammation (i.e. gastritis). There is a decreasing incidence of this type of stomach cancer

risk factors for intestinal type:

H.Pylori infection
male sex
older age
inflammation (e.g. from ulcers)

2) Diffuse-Type: 32% of cases

less localized to a specific area of stomach, infiltrates deeper layers of stomach, making it harder to diagnose endoscopically
Since diffuse stomach cancer is hard to diagnose endoscopically, the Cambridge Protocol Screening recommends 5 biopsies from 6 locations in the stomach (a minimum of 30 biopsies in the stomach)
cause is not clearly understood
increasing incidence
more likely to be found in proximal stomach (closer to esophagus)
younger age of onset
cancer cells take on a “Signet ring” shape
risk factors unclear: not gender specific; may be associated with H.Pylori infection

Helicobacter Pylori (H. Pylori) Infection

Is a bacteria that grows in the digestive tract; can be harmless but may attack the stomach lining and cause ulcers
50% of the world population carries this infection
In Ontario: 29.4% in men, 14.9% women
Risk Factors: age, First Nation, living with someone infected with H. Pylori, poor sanitation, overcrowding, higher incidence in Japan, Korea, China

Stomach Cancer Risk Factors:

Aging
Geographic location
Smoking
Diet?
Gastritis (Inflammation from Helicobacter pylori)
Intestinal metaplasia (change in cell form)
Gastric polyps (adenoma)
Chronic gastric ulcer
Pernicious anemia
Blood group – Type A

Introduction to Genetics:

Cells contain chromosomes which are made up of multiple genes (DNA segments). Genes encode proteins that are the building blocks for all the cells in the body
Tumors result from an abnormal proliferation of cells
All cancer is genetic, but NOT all cancer is hereditary. All cancers have mutated genes (genetic) but not all these genes are passed on (hereditary). Some gene mutations occurs sporadically (random mutation), other mutations are inherited.
Most cancers are sporadic (random, not hereditary); some cancers show family clusters but a gene has not been identified; a small percent of cancers can be called hereditary where one or more genes have been identified as causing the cancer

Sporadic Gene Mutation

·        NOT hereditary gene mutation that causes cancer
·        for example an individual with a single sporadic HER2/neu gene mutation may have an ulcer, metaplasia or no symptoms. If both genes are affected a malignant tumor will occur
·        HER2/neu gene mutation can cause an overabundance of proteins (tumor).
·        If this gene mutation is identified, targeted treatment (Herceptin), can be used to block the HER2 receptor and prevent abnormal cell proliferation

Hereditary Cancer

Sporadic (non-hereditary) cancer is much more common that hereditary cancer. There are certain criteria that make a person eligible for genetic testing in Canada.
A person may inherit one gene from their parents. This person may acquire a second mutation in their lifetime that results in cancer
Hereditary cancers affect multiple people in one family through many generations. These people tend to be diagnosed with cancer at a younger age.

1. Hereditary Diffuse Gastric Cancer Syndrome (CDH1 )

Most common type of hereditary cancer
Only 8 to 12% of individuals with gastric cancer have a CDH1 mutation (therefore hereditary cancer is rare)
CDH1 gene mutation results in an overabundance of E-cadherin proteins and cell-to-cell adhesion, leading to tumor formation.
50% inheritance pattern: a first-degree relative has a 50% chance of passing on the mutated gene
By age 80, there is a 70% chance of stomach cancer in men and a 56% chance in women who carry the CDH1 mutation
CDH1 mutation is also associated with other cancer risk such as lobular breast cancer in women
· Patients with this mutation require screening (Cambridge Protocol screening with a minimum of 30 biopsies taken at 6 locations in the stomach)
Prophylactic total gastrectomy (stomach removal surgery) is recommended for CDH1 carriers after age 20
Annual endoscopy by age 20
May require prophylactic mastectomy

2. CTNNA1-Associated Diffuse gastric cancer

The CTNNA1 gene mutation interacts with CDH1 to disrupt cadherin-1 protein
This mutation is more rare than CDH1 mutation but has been linked to increased risk of gastric cancer

3. Lynch Syndrome

A hereditary mutation that puts the patient at risk for many kinds of cancer.
Most at risk for colorectal and endometrial cancer
There are 5 genes called “mismatch repair genes” (MMR genes) that are associated with Lynch syndrome
MMR genes are inherited from your parents
There are 2 copies of MMR genes
Mismatch repair genes check DNA for errors (mutations). If an error is found the body will act to repair the error
If your parent has Lynch syndrome, they can pass on 1 mutated MMR gene to you. If both MMR genes become mutated then the body loses its ability to repair DNA errors
Cells start to accumulate too many mistakes and start growing too fast and not die when they should. This can lead to cancer.
A person with Lynch syndrome is at risk for many kinds of cancers. Colorectal and endometrial are most common. Other cancers include ovarian, stomach, skin, urinary tract, small bowel, pancreas, biliary tract and central nervous system
To test for Lynch syndrome the tumor can be biopsied
New immunotherapies are being developed for Lynch syndrome
A person with Lynch syndrome should be screened regularly. Please refer to the PowerPoint for screening guidelines

4. Polyposis Conditions

There are 3 types of polyposis conditions
The Peutz-Jaghers type can put a person at risk for many types of cancer, including stomach cancer

5. Other

· Hereditary Breast-Ovarian Cancer syndrome: BRACA1 and 2 increase the risk of breast and ovarian cancers. There has been a link to stomach cancer but this link is still under investigation

· Li-Fraumeni Syndrome: This gene increases the risk for childhood brain, sarcoma and early onset breast cancer. There has been a link to stomach cancer but this link is still under investigation