Genetics & Hereditary Conditions
Genetic mutations play a role in the development of all cancers. Most cancers are caused by gene changes that happen during a person’s lifetime, but a person’s cancer risk can be higher if they have one of these rare inherited mutations. Doctors can test for certain kinds of gene changes that make a person more likely to get cancer. A genetic counselor, doctor, or other health care professional trained in genetics can help an individual or family understand genetic test results.
There are several inherited or hereditary conditions that may increase the likelihood that the person will get cancer. Some of them include:
- Hereditary diffuse gastric cancer
- Lynch syndrome or hereditary non-polyposis colorectal cancer (HNPCC)
- Familial adenomatous polyposis (FAP)
- BRCA1 and BRCA2
- Li-Fraumeni syndrome
- Peutz-Jeghers syndrome (PJS)
Hereditary Diffuse Gastric Cancer
One of these hereditary conditions is Hereditary Diffuse Gastric Cancer (HDGC). Here are some common questions that are asked about HDGC and the answers but always consult with your healthcare provider for more information and for more specifics about your disease and situation.
What is Hereditary Diffuse Gastric Cancer?
Hereditary diffuse gastric cancer (HDGC) is an inherited condition associated with an increased risk of stomach (gastric) cancer. Diffuse gastric cancer is a specific type of stomach cancer that tends to affect much of the stomach rather than staying in one area of the stomach. The average age for someone with HDGC to be diagnosed with stomach cancer is 38, although it can be diagnosed much earlier or later than that. Women with HDGC also have an increased risk of lobular breast cancer. People with HDGC may also have some increased risk of colorectal cancer.
What causes HDGC?
HDGC is a genetic condition. This means that the cancer risk and other features of HDGC can be passed from generation to generation in a family. The gene associated with HDGC is called CDH1. A mutation (alteration) in the CDH1 gene gives a person an increased risk of developing stomach cancer as well as other cancers associated with HDGC. Researchers believe that other genes may also be associated with HDGC, and studies are ongoing to learn more. Ask your healthcare provider about this or contact us at Debbie’s Dream for more information.
How is HDGC inherited?
Normally, every cell has two copies of each gene: one inherited from the mother and one inherited from the father. HDGC can be passed from a parent to an offspring. HDGC follows an autosomal dominant inheritance pattern, in which a mutation happens in only one copy of the gene. This means that a parent with a gene mutation may pass a copy of their normal gene or a copy of the gene with the mutation to their offspring. Therefore, a child who has a parent with a mutation has a 50% chance of inheriting that mutation. A brother, sister, or parent of a person who has a mutation also has a 50% chance of having the same mutation.
How common is HDGC?
The overall incidence of gastric cancer varies in different parts of the world. In the United States, it is estimated that less than 1% of the population will develop stomach cancer. The highest rates of gastric cancer are found in China, Japan, and other countries in Southeast Asia, as well as in Central and South America. The specific number of families with HDGC is unknown but it is estimated that only approximately 1% of all stomach cancers are caused by a mutation in the CDH1 gene.
How is HDGC diagnosed?
Guidelines for the diagnosis of HDGC syndrome have been proposed, but may change over time as more is learned about this condition. Currently, the diagnosis of HDGC is suspected if a person or family members meet any of the criteria listed below:
- At least two cases of stomach cancer in a family, with at least one being diffuse gastric cancer and diagnosed before age 50
- At least three cases of stomach cancer at any age in a family, with at least one being diffuse gastric cancer
- A person diagnosed with diffuse gastric cancer before age 45
- A person diagnosed with both diffuse gastric cancer and lobular breast cancer
- A person diagnosed with diffuse gastric cancer and another family member diagnosed with lobular breast cancer
- A person diagnosed with diffuse gastric cancer and another family member diagnosed with signet cell adenocarcinoma of the colon
Genetic testing for mutations in the CDH1 gene is available. However, it is estimated that only about 30% of families that appear to have HDGC will have a mutation in the CDH1 gene. Therefore, both clinical and genetic aspects must be considered in counseling individuals about the potential for their family to have HDGC, and talking with a genetic counselor or geneticist (a doctor with training in genetic diseases and conditions) that is familiar with the syndrome is recommended.
What are the estimated cancer risks associated with HDGC?
In people who have a mutation in the CDH1 gene, the lifetime risk for advanced diffuse gastric cancer is estimated to be greater than 80% for men and women by age 80. Women with a mutation in theCDH1 gene have about a 60% risk of developing lobular breast cancer by age 80. There is also a higher risk of colorectal cancer in people with HDGC.
What are the screening options for HDGC?
Screening for stomach cancer is suggested for people known to be at risk for HDGC. However, the effectiveness of current screening techniques for the early diagnosis of stomach cancer is not proven. Screening recommendations may also change over time as new technologies are developed and more is learned about HDGC. It is important to talk with your doctor about appropriate screening tests.
Current Screening Options:
- Endoscopy (also known as an upper gastrointestinal [GI] study; this procedure uses a thin, flexible tube with a light inserted into the body to examine a specific region)
- Chromoendoscopy (endoscopy using dye to help detect cancer)
- Endoscopic ultrasound(which uses sound waves to find a tumor in the body)
Additional Screening for Women:
Women at risk for HDGC should be considered at high risk for breast cancer and should talk with their doctor about breast cancer screening options at the age of 35, or ten years before the age of the youngest affected relative. Screening options include:
- Monthly breast self-examinations
- Clinical breast examinations (examination by a doctor or nurse) every six months
- Regular breast imaging with mammograms, ultrasound, and magnetic resonance imaging (MRI).
Colonoscopy, every one to two years, should be considered in families where both gastric cancer and colorectal cancer have been diagnosed. Colorectal cancer screening should begin five to 10 years earlier than the earliest diagnosis of colorectal cancer in the family or by age 50, whichever is sooner.
Questions to Ask Your Doctor
If you are concerned about your risk of cancer, talk with your doctor. Consider asking the following questions of your doctor:
- What is my risk of developing stomach cancer?
- What is my risk of developing other types of cancer?
- What can I do to reduce my risk of cancer?
- What are my options for cancer screening?
If you are concerned about your family history and think you or other family members may have HDGC, consider asking the following questions:
- Does my family history increase my risk of stomach cancer?
- Does my family history increase the chances of others in my family getting stomach cancer?
- Does my family history increase my risk of getting other types of cancer?
- Does my family history increase the chances of others in my family getting other types of cancer?
- Should I meet with a genetic counselor?
- Should other members of my family meet with a genetic counselor?
- Should I consider genetic testing?
- Should other members of my family consider genetic testing?
Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC), is a type of inherited cancer of the digestive tract. People who have Lynch syndrome have a significantly increased risk of developing colorectal cancer and an increased risk of developing other types of cancers such as endometrial (uterine), stomach, breast, ovarian, small bowel (intestinal), pancreatic, prostate, urinary tract,liver, kidney, and bile duct cancers. Lynch syndrome may be a possible diagnosis when there are multiple cases of colorectal cancer on the same side of the family. There is also an increased risk of a person with Lynch syndrome to develop multiple cancers during his or her lifetime.
In addition, cancer is more likely to be diagnosed at a young age. The average age for colorectal cancer to be diagnosed in someone with Lynch syndrome is 45, as compared with the average age of 72 for a new diagnosis of colorectal cancer in the general population. In Lynch syndrome, colorectal cancer is somewhat more likely to develop on the right side of the colon.
The classic diagnostic criteria for Lynch syndrome are called the Amsterdam Criteria. Over time, the Amsterdam Criteria have been modified to include the variety of cancers that are seen in Lynch syndrome families. The Modified Amsterdam Criteria, also known as the Amsterdam II Criteria, are listed below:
- Three or more relatives with a Lynch syndrome-related cancer;* one relative must be a first-degree relative (parent, brother, sister, or child) of the other two
- At least two generations with cancer (such as a parent and child)
- One or more cases of cancer diagnosed younger than age 50
- Familial adenomatous polyposis (FAP) is ruled out as the cause
*(colorectal cancer, endometrial cancer, small bowel, ureter, or renal pelvis cancer; some people would also consider including ovarian cancer)
The definition of Lynch syndrome is still evolving. A family may still have Lynch syndrome even if the Amsterdam Criteria does not fully match the family history. Therefore, meeting with a health professional who specializes in genetics, such as a genetic counselor or medical geneticist (a doctor with training in genetic diseases and conditions), is recommended for people who have a family history that suggests Lynch syndrome.
What causes Lynch syndrome?
Lynch syndrome is a genetic condition. This means that the cancer risk can be passed from generation to generation in a family. Several genes have been identified that are linked to Lynch syndrome. They include MLH1, MSH2, MSH6, PMS2, and EPCAM. A mutation (alteration) in any of these genes gives a person an increased lifetime risk of developing colorectal cancer and other related cancers. Women also have an increased risk of developing endometrial and ovarian cancers.
Most mutations that cause Lynch syndrome are found in the MLH1 or MSH2 genes. Not all families that appear to have Lynch syndrome will have mutations in MLH1, MSH2, MSH6, PMS2, or EPCAM. Research is ongoing to identify other genes associated with Lynch syndrome. Some people will develop changes in these genes that are not inherited but are related to the aging process and other causes that are not well understood. If a tumor is found to have alterations in these genes, the person’s blood will also be tested for that abnormal gene. If the blood and tumor both have the changed gene, the condition is inherited rather than acquired, meaning other family members could be affected; testing is available (see below).
How is Lynch syndrome inherited?
Normally, every cell has two copies of each gene: one inherited from the mother and one inherited from the father. Lynch syndrome follows an autosomal dominant inheritance pattern, in which a mutation needs to happen in only one copy of the gene for the person to have an increased risk of getting that disease. This means that a parent with a gene mutation may pass along a copy of their normal gene or a copy of the gene with the mutation. Therefore, a child who has a parent with a mutation has a 50% chance of inheriting that mutation. A brother, sister, or parent of a person who has a mutation also has a 50% chance of having the same mutation.
How common is Lynch syndrome?
Most colorectal cancer is sporadic (occurs by chance with no known cause). Approximately 3% to 5% of all cases of colorectal cancer are thought to be due to Lynch syndrome.
How is Lynch syndrome diagnosed?
Lynch syndrome is likely if a family history meets the Modified Amsterdam Criteria listed above. Lynch syndrome can be confirmed through a blood test. The test can determine if someone has a mutation in one of the genes associated with Lynch syndrome. Currently, testing is available for the MLH1, MSH2, MSH6, and EPCAM genes. The PMS2 gene is tested for in some clinical trials (research studies) as well as cancer centers that specialize in Lynch syndrome. However, not all families with Lynch syndrome will have a mutation in one of these genes.
For patients who have a family history that suggests Lynch syndrome, screening tests can be performed on tumor (cancer) tissue to help determine if Lynch syndrome is likely. The two screening tests suggested are microsatellite instability testing (MSI) and immunohistochemistry testing (IHC). The results of these tests can indicate whether more specific genetic testing should be considered.
Since most colorectal cancer is sporadic, genetic testing is only recommended for people who have a family history that suggests Lynch syndrome. Testing for mutations in the Lynch syndrome genes may not be beneficial for the average person.
What are the estimated cancer risks associated with Lynch syndrome?
General cancer risks for people with Lynch syndrome
- Colorectal cancer 80%
- Stomach cancer 11% to 19%
- Hepatobiliary tract cancer (liver/bile duct) 2% to 7%
- Urinary tract cancer 4% to 5%
- Small bowel cancer (intestines) 1% to 4%
- Brain or central nervous system tumor 1% to 3%
Cancer risks for women with Lynch syndrome
As noted above, Lynch syndrome has been linked to higher risk of other types of cancer as well, including pancreatic, prostate, kidney, and breast cancers.
What are the screening options for Lynch syndrome?
It is important to discuss with your doctor the following screening options, as each individual is different:
General screening guidelines
- Colonoscopy every one to two years, beginning between the ages of 20 to 25 (or five years younger than the earliest age at diagnosis in the family, whichever is sooner)
- Periodic upper endoscopy screening (this procedure uses a thin, flexible tube with a light inserted into the body to examine a specific region) for stomach or intestinal cancer (especially if a family member has had one of these cancers)
- Yearly urine cytology to screen for urinary tract cancer
Screening for women
- Yearly pelvic examination, Pap test, transvaginal ultrasound (a test where a small ultrasound probe is inserted for a pelvic examination in order to obtain better imaging of the uterus), endometrial biopsy (an examination on a sample of tissue from the inner lining of the uterus done as part of a pelvic examination), and CA-125 blood test (a test to detect a protein found to be elevated in the blood of some women with ovarian cancer), beginning between the ages of 25 to 30
Screening options may change over time as new technologies are developed and more is learned about Lynch syndrome. It is important to talk with your doctor about appropriate screening tests
Learn more about what to expect with common tests and procedures.
Questions to ask the doctor
If you are concerned about your risk of colorectal cancer or other types of cancer, talk with your doctor. Consider asking the following questions of your doctor:
- What is my risk of developing colorectal cancer or other types of cancer?
- What can I do to reduce my risk of cancer?
- What are my options for cancer screening?
If you are concerned about your family history and think your family may have Lynch syndrome, consider asking the following questions: