What is Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer)?
Colorectal cancer is the third most common type of cancer and the second leading cause of cancer-related deaths in the United States. It’s estimated that in 2023, there will be 152,020 new cases and 52,550 deaths. While most colorectal cancers happen randomly, about 5% to 10% are due to inherited gene mutations. The most common inherited form is called Lynch syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC).
People with Lynch syndrome are key to identify because they have a very high chance of developing colorectal cancer – up to 80% – and a 60% chance of developing endometrial cancer, which is cancer of the lining of the uterus. They are also more likely to have other types of cancer such as stomach, ovarian, small intestine, urothelial (involving the ureter, renal pelvis, and bladder), prostate, bile duct, pancreas, adrenal gland, brain cancers (glioblastoma), sebaceous gland adenomas, and keratoacanthomas.
Lynch syndrome was discovered by a medical intern named Henry Lynch in 1962. He learned about a young hospitalized farm worker who was certain he would die young of cancer because of its prevalence in his family. Intrigued by this, Dr. Lynch decided to investigate. He purchased a camper van and turned it into a basic laboratory. For the next two years, he travelled around rural Nebraska, Kansas, and Missouri during weekends. He gathered medical records, histories, pathology reports, and blood samples from the patient’s extended family members. He found out that a lot of them died from colon cancer before they were 50.
Despite Dr. Lynch finding no other possible explanation except for inherited genetics, he struggled to receive grants for further investigation as the general medical community believed these cancers were due to environmental causes. His theories were mainly dismissed until the 1980s when advancements in molecular genetics techniques led to the discovery of the mismatch repair gene deficiencies and related microsatellite instabilities in these heritable cancers. In honor of his work, HNPCC was renamed Lynch syndrome in 1984. Today, Dr. Lynch is celebrated for his contributions to cancer genetics, including identifying the breast-ovarian cancer syndrome and the BRCA genes, and pioneering the entire field of cancer genomics.
What Causes Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer)?
Lynch syndrome is caused by a mutation or change in one of four specific genes involved in DNA repair: MLH1, MSH2, MSH6, and PMS2. Sometimes, alterations in a gene called EPCAM can also result in Lynch syndrome by interrupting the function of the MSH2 gene.
Normally, these DNA repair genes help fix mistakes that happen when DNA is being copied, a process essential for cell growth and division. When these genes aren’t working properly due to mutations, these defects aren’t corrected, which can lead to the cells behaving abnormally and increasing the risk of developing cancer. This disruption in DNA repair is known as microsatellite instability (MSI).
However, it’s important to note that there are different causes for high levels of MSI – it’s not always due to Lynch syndrome. A common cause for MSI in people without the syndrome is methylation, which is essentially a switch that turns the MLH1 gene off. So, if someone is found to have high MSI, further tests are needed to understand the exact reason.
Now, regarding Lynch syndrome, a person is born with two copies of each gene – one from each parent. If someone has Lynch syndrome, it means they have one normal gene and one mutated gene. The mutation doesn’t become a problem until the normal gene gets altered or damaged. Rarely, a person does not have Lynch syndrome at birth but acquires mutations in both copies of the gene later, resulting in a loss of the DNA repair proteins and the same increased cancer risk.
Lynch syndrome is passed from parents to their children. This means that if a parent has Lynch syndrome, each of their children has a 50% chance of also inheriting the syndrome.
Risk Factors and Frequency for Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer)
Lynch syndrome is associated with several types of cancer, but colorectal cancer and endometrial cancer are the most common. Lynch syndrome is present in 2-4% of all colorectal cancer cases and roughly 2.5% of endometrial cancer cases. This means that Lynch syndrome is the cause of 1 in 35 cases of colorectal cancer and 1 in 50 cases of endometrial cancer. People with Lynch syndrome are usually diagnosed with colorectal cancer between the ages of 44 and 61, and with endometrial cancer between the ages of 48 and 62. Each year, it’s estimated that around 12,000 Americans are diagnosed with Lynch syndrome when they are properly screened.
Signs and Symptoms of Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer)
Lynch syndrome is a genetic condition that increases the risk of several types of cancer including colon, endometrial, ovarian, upper digestive tract, urinary tract, prostate, pancreas, and brain. It’s important to know one’s family and personal medical history to spot the risk of Lynch syndrome. Those who have a high likelihood of having the condition should have a series of tests, such as immunohistochemical and/or microsatellite analysis, followed by germline DNA analysis for a conclusive diagnosis.
There are two main sets of criteria used to screen for Lynch syndrome: the Amsterdam II Criteria and the Revised Bethesda Guidelines. Initially, the focus was only on colon tumors, but this has been expanded to include cancers of the endometrium, small intestine, ureter, and kidney. They also gave added emphasis to microsatellite instability (MSI) to aid in identifying more people with the condition.
These screening criteria consider factors such as colorectal cancer with MSI, other cancers associated with Lynch syndrome, the age at diagnosis, and affected family members. However, due to the different genes involved in Lynch syndrome, not everyone with the condition will meet these criteria. Each gene involved presents a different level of risk, and depending on which gene is affected, the disease pattern in a family may not strictly follow these criteria.
- Increased risk of various types of cancer
- Significance of personal and family medical history
- Need for specific diagnostic tests
- The Amsterdam II Criteria and Revised Bethesda Guidelines for screening
- Inclusion of additional cancers in the screening criteria
- Variability in the disease presentation depending on the gene affected
Testing for Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer)
For diagnosing Lynch syndrome, which is a genetic condition that increases the risk of various types of cancer, doctors usually order several tests. These include a test called polymerase chain reaction (PCR), immunohistochemical staining (IHC), and germline sequencing. They are used to check for changes in specific proteins and genes. If these tests indicate the possibility of Lynch syndrome, genetic testing may be suggested.
PCR helps identify Microsatellite instability (MSI), a condition that occurs due to a failure in the body’s DNA repair mechanism. MSI can be confirmed through examining changes in the length of specific DNA sequences in a sample of the tumor’s DNA.
Immunohistochemical staining (IHC) is another important test. It uses certain antibodies to detect proteins responsible for DNA repair within the tumor cells. If these proteins are missing (indicating a DNA repair deficiency), this can suggest the possibility of Lynch syndrome.
However, it’s worth remembering that these tests are not fool-proof and may sometimes give false-negative results. If certain protein deficiencies, such as MLH1, show up on the IHC test, other tests are conducted as well to distinguish between Lynch syndrome and sporadic colorectal cancer.
Guidelines by the National Comprehensive Cancer Network recommend that individuals under 70 with colorectal cancer and those over 70 meeting specific criteria, along with those under 50 with endometrial cancer, undergo IHC staining of the mismatch repair proteins. Genetic counseling is recommended before genetic testing is done because the results can have important implications for the patient and their family.
Prior to testing for Lynch syndrome, a thorough family cancer history is collected, detailing any instances of cancer in three generations of relatives. Testing should be considered for patients who meet certain criteria, such as particular diagnostic criteria known as the Amsterdam II Criteria or Revised Bethesda Guidelines, or having confirmed Lynch syndrome in the family. There are also tests to estimate the risk of Lynch syndrome.
In summary, diagnosing Lynch syndrome involves a multi-step process of laboratory tests, medical and family history evaluation, and potentially genetic testing. Identifying patients at risk for Lynch syndrome is important for implementing preventative measures and regular screening for related cancers.
It’s also worth noting that Familial Adenomatous Polyposis (FAP) is a separate but similar genetic condition that increases the risk for colorectal cancer. FAP is typically identified by the presence of a large number of polyps in the colon and requires different treatment approaches, often involving surgery.
Treatment Options for Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer)
If you have a mutation associated with Lynch syndrome, you have a higher chance of developing certain types of cancer, especially colorectal, endometrial (which affects the lining of the uterus), gastric (stomach), and ovarian cancers. People with MSH6 or PMS2 mutations associated with Lynch syndrome may have a lower risk of endometrial and ovarian cancer.
Here’s what medical guidelines suggest for managing Lynch syndrome:
For your colon:
– You should start having a colonoscopy, a procedure that lets your doctor look at the inner lining of your large intestine, by age 20 to 25 and repeat it every 1 to 2 years, or possibly earlier if a family member was diagnosed at a young age.
– If you are diagnosed with colon cancer, or if doctors find a severe adenoma (a non-cancerous tumor that could develop into cancer) that they can’t remove in another way, you might need a colectomy, a surgery to remove part or all of your colon.
– If you can’t follow the recommended monitoring measures, doctors might also suggest a colectomy.
For your endometrium, uterus, and ovaries:
– Starting at age 30, you should get a yearly pelvic exam, transvaginal ultrasound, endometrial sampling, and a blood test for a protein called CA-125.
– If you have abnormal uterine or vaginal bleeding, get it checked out immediately.
– After you’re done having children, you might consider surgery to remove your uterus and ovaries.
While it’s difficult to prevent all Lynch syndrome-related cancers, here’s what doctors recommend based on your family’s specific cancer history:
– You might need an upper endoscopy, a procedure that lets your doctor look at the inside of your upper digestive tract, every 1 to 3 years starting in your 30s. This is especially important if you’re of Asian descent, have a family history of related cancers, or test positive for H.Pylori, a bacteria that can cause infections in the stomach.
– You might also need to start regular urine tests in your 30s to check for urinary tract cancers. Smoking increases your risk for these.
Finally, there’s medication:
– Some studies suggest that nonsteroidal anti-inflammatory drugs, like aspirin, might help reduce the risk of colon cancer in people with Lynch syndrome. But the specifics, like how much to take and for how long, still aren’t clear.
– Some medications, like monoclonal antibodies (which are designed to attach to specific cells and stimulate an immune response), are being studied for their ability to treat these cancers by triggering an immune response.
Remember, your diagnosis also matters for your family members, who might also be at risk for Lynch syndrome. Make sure to talk to them about their potential cancer risk and the importance of regular testing, monitoring, and preventive care.
What else can Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) be?
Lynch syndrome-related cancers can sometimes present the same way as cancers caused by spontaneous mutations. This means that they can be difficult to tell apart. Lynch syndrome happens due to certain genetic mutations and makes people more susceptible to a range of cancers. Distinguishing between Lynch syndrome and other causes is important because treatment options and outlook may vary.
During the process of diagnosing cancers linked with Lynch syndrome, there are other conditions that doctors might consider. These include:
- Attenuated familial adenomatous polyposis
- Cowden disease
- Cronkite-Canada syndrome
- Familial adenomatous polyposis
- Clusters of late-onset colorectal tumors that run in families
- Hyperplastic polyps
- Juvenile polyposis syndrome
- Lymphomatous polyposis
- Muir-Torre syndrome
- Nodular lymphoid hyperplasia
- Common colon cancer
- Turcot syndrome
- Smoking-related bladder cancer
What to expect with Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer)
People with Lynch syndrome, a condition that increases the risk of developing certain types of cancers, often have a lower-than-average life expectancy. This is mainly because the likelihood of developing cancer, particularly colon cancer, increases with this condition, and it can also show up earlier in life. Despite these challenges, the 10-year overall survival rates for those with Lynch syndrome who develop rectosigmoid malignancies (a type of colorectal cancer) is quite high at 70%. In the case of colon cancer, the survival rate jumps to 88%.
Regular colorectal cancer screening can increase these survival rates even more. A more aggressive surgical approach to removing parts of the colon impacted by this syndrome, such as a total colectomy (removal of the entire colon) versus a hemicolectomy (removal of only part of the colon), can further enhance a patient’s chances of being cancer-free.
However, it’s important to note that after partial removal of the colon, the risk of colorectal cancer recurring in Lynch syndrome patients can still be significant. It has been estimated that over a course of 10 years, the risk is about 16%. This risk increases with time, estimated at 41% by 20 years, and 62% at 30 years.
Possible Complications When Diagnosed with Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer)
Lynch syndrome doesn’t have any unique complications aside from a heightened likelihood and earlier onset of associated cancers. It’s also expected for individuals with this syndrome to have an increased occurrence of simultaneous and sequential tumors.
Common manifestations related to Lynch Syndrome:
- Increased frequency of associated cancers
- Early onset of these cancers
- Simultaneous tumors
- Sequential tumors
Preventing Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer)
If a patient’s family history indicates a risk for genetic diseases, it’s important for the rest of the family to consider genetic counseling and testing. This is especially important for kids; testing is generally suggested about 10 years before the age at which the earliest family member developed cancer, although ideally, they should be tested no later than when they’re 20 to 30 years old. If family members don’t have any genetic abnormalities in their germline (i.e., the cells that pass on their genes), it might still be a good idea for them to be monitored because they are close family members of the patient.
