Lynch syndrome, often called hereditary nonpolyposis colorectal cancer (HNPCC), is an inherited disorder that increases the risk of many types of cancer, particularly cancers of the colon (large intestine) and rectum, which are collectively referred to as colorectal cancer. People with Lynch syndrome also have an increased risk of cancers of the stomach, small intestine, liver, gallbladder ducts, urinary tract, brain, and skin. Additionally, women with this disorder have a high risk of cancer of the ovaries and lining of the uterus (endometrial cancer). Women with Lynch syndrome have a higher overall risk of developing cancer than men with the condition because of these cancers of the female reproductive system. In individuals with Lynch syndrome who develop cancer, the cancer typically occurs in their forties or fifties.

People with Lynch syndrome may occasionally have noncancerous (benign) growths in the colon, called colon polyps. In individuals with this disorder, colon polyps occur at a younger age but not in greater numbers than they do in the general population.

Colon cancer, a malignant tumor of the large intestine, affects both men and women. In the United States, approximately 160,000 new cases of colorectal cancer are diagnosed each year.

What do we know about heredity and colon cancer?

Colon cancer, a malignant tumor of the large intestine, affects both men and women. In the United States, approximately 160,000 new cases of colorectal cancer are diagnosed each year.

The majority of colon cancer cases are sporadic, which means a genetic mutation may happen in that individual person. However, approximately 5 percent of individuals with colon cancer have a hereditary form, which means that they have inherited a mutation from one of their parents that causes the disease. In those families, the chance of developing colon cancer is significantly higher than in the average person. These hereditary cancers typically occur at an earlier age than sporadic (non-inherited) cases of colon cancer. The risk of inheriting these mutated genes from an affected parent is 50 percent for both males and females.

Scientists have discovered several genes contributing to a susceptibility to two types of colon cancer:

• FAP (familial adenomatous polyposis)
  So far, only one gene has been discovered that leads to FAP: the APC gene, located on human chromosome 5. However, over 300 different mutations have been identified in this APC gene. Individuals with this syndrome develop many polyps in their colon. People who inherit mutations in this gene have a nearly 100 percent chance of developing colon cancer by age 40.

• HNPCC (hereditary nonpolyposis colon cancer) also called Lynch Syndrome
  Individuals with an HNPCC gene mutation have an estimated 80 percent lifetime risk of developing colon or rectal cancer. However, these cancers account for only three to five percent of all colorectal cancers. So far, five HNPCC genes have been discovered:

  • MSH2 on chromosome 2

  • MLH1 on chromosome 3

  • PMS2 on chromosome 7

  • MSH6 on chromosome 2

  • PMS1 on chromosome 2

Mutations in MSH2 and MLH1 are the most common mutations that cause HNPCC. A mutation in PMS1 was originally reported in a single family with HNPCC, however, this mutation was not found in all members of the family who had developed the disease. For this reason, the role of PMS1 in HNPCC is currently being questioned.

The genes that cause HNPCC and FAP were relatively easy to discover because they exert strong effects. Other genes that cause susceptibility to colon cancer are harder to discover because the cancers are caused by a number of genes, each of which individually exerts a weak effect.

Is there a test for hereditary colon cancer?

Gene testing can identify individuals who carry the more common gene mutations associated with FAP or HPNCC, such as those listed above. However, these tests may not identify all gene mutations that cause FAP or HNPCC. In some families, additional mutations may be present that cause the FAP or HNPCC, which cannot be detected by the commonly used gene tests.

The test for FAP syndrome involves examining DNA in blood cells called lymphocytes (white blood cells), looking for mutations in the APC gene. No treatment to reduce cancer risk is currently available for people with APC mutations that are associated with FAP. But for those who test positive, frequent surveillance can detect the cancer at an early, more treatable stage. Because of the early age at which this syndrome appears, the test may be offered to children under the age of 18 if they have a parent known to carry the mutated APCgene.

Researchers hope that an easier test, which is currently experimental, will become available for common use in three to five years. This new test looks for cancer cells with the APC mutation in a stool sample.

Genetic testing for HNPCC involves looking for mutations in four of the five genes identified that are associated with HNPCC - MLH1, MSH2, MSH6, and PMS2.

Individuals in families at high risk of genetic predisposition may consider testing. Genetic counselors can help individuals make decisions regarding testing.

In the United States, it is estimated that 1 in 279 individuals have a genetic variant (also known as a mutation) associated with Lynch syndrome.

Changes in the MLH1, MSH2, MSH6, PMS2, or EPCAM gene have been found in people with Lynch syndrome.

The MLH1, MSH2, MSH6, and PMS2 genes are involved in repairing errors that occur when DNA is copied in preparation for cell division (a process called DNA replication). Because these genes work together to fix DNA errors, they are known as mismatch repair (MMR) genes. Variants in any of these genes prevent the proper repair of DNA replication errors. As the abnormal cells continue to divide, the accumulated errors can lead to uncontrolled cell growth and possibly cancer. Variants in the MLH1 or MSH2 gene tend to lead to a higher risk (70 to 80 percent) of developing cancer in a person's lifetime, while variants in the MSH6 or PMS2 gene have a lower risk (25 to 60 percent) of cancer development.

Variants in the EPCAM gene also lead to impaired DNA repair, although the gene is not itself involved in this process. The EPCAM gene lies next to the MSH2 gene on chromosome 2 and certain EPCAM gene variants cause the MSH2 gene to be turned off (inactivated). As a result, the MSH2 gene's role in DNA repair is impaired, which can lead to accumulated DNA errors and cancer development.

Although variants in these genes predispose individuals to cancer, not all people with these variants develop cancerous tumors.

Normal Function

The MLH1 gene provides instructions for making a protein that plays an essential role in repairing DNA. This protein helps fix errors that are made when DNA is copied (DNA replication) in preparation for cell division. The MLH1 protein joins with another protein called PMS2 (produced from the PMS2 gene), to form a two-protein complex called a dimer. This complex coordinates the activities of other proteins that repair errors made during DNA replication. The repairs are made by removing a section of DNA that contains errors and replacing the section with a corrected DNA sequence. The MLH1 gene is one of a set of genes known as the mismatch repair (MMR) genes. The MLH1 protein can also form a dimer with the MLH3 or PMS1 protein (each produced from different genes), but the function of these dimers is not well understood.

Health Conditions Related to Genetic Changes

Constitutional mismatch repair deficiency syndrome

About 10 variants (also known as mutations) in the MLH1 gene have been associated with condition called constitutional mismatch repair deficiency (CMMRD) syndrome. Individuals with this condition are at increased risk of developing cancers of the colon (large intestine) and rectum (collectively referred to as colorectal cancer), brain, and blood (leukemia or lymphoma). These cancers usually first occur in childhood, with the vast majority of cancers in CMMRD syndrome diagnosed in people under the age of 18. Many people with CMMRD syndrome also develop changes in skin coloring (pigmentation), similar to those that occur in a condition called neurofibromatosis type 1.

Individuals with CMMRD syndrome inherit two MLH1 gene variants, one from each parent, while people with Lynch syndrome (described below) have a variant in one copy of the MLH1 gene.

MLH1 gene variants result in near or complete loss of MLH1 protein production. A shortage of this protein eliminates mismatch repair activity and prevents the proper repair of DNA replication errors. These errors accumulate as the abnormal cells continue to divide. The errors disrupt other genes involved in important cellular processes, such as controlling cell growth and division (proliferation). If cell growth is uncontrolled, it can lead to childhood cancer in people with CMMRD syndrome.

It is thought that the features of neurofibromatosis type 1 in people with CMMRD syndrome are due to genetic changes in the NF1 gene that result from loss of mismatch repair. These changes are present only in certain cells (somatic variants), whereas NF1 gene variants that are present in all cells of the body cause neurofibromatosis type 1.

Lynch syndrome

About 40 percent of all cases of Lynch syndrome with an identified gene alteration are associated with inherited variants in the MLH1 gene. Several hundred MLH1 gene variants have been found in people with this condition. Lynch syndrome increases the risk of many types of cancer, particularly colorectal cancer. People with Lynch syndrome also have an increased risk of cancers of the endometrium (lining of the uterus), ovaries, stomach, small intestine, gallbladder ducts, upper urinary tract, and brain. By age 75, the risk of developing one of these cancers is 80 percent for women and 70 percent for men with an MLH1 gene variant.

MLH1 gene variants involved in this condition prevent the production of the MLH1 protein from one copy of the gene or lead to an altered version of this protein that does not function properly. A decrease in functional MLH1 protein leads to an increase in unrepaired DNA errors during cell division. The errors accumulate as the cells continue to divide, which may cause the cells to function abnormally, increasing the risk of tumor formation in the colon or another part of the body.

Because there is some functional MLH1 protein produced from the normal copy of the gene, mismatch repair activity in Lynch syndrome is reduced but not absent, as it is in CMMRD syndrome (described above). This difference in DNA repair activity levels likely explains why cancers in Lynch syndrome generally develop in adulthood while those in CMMRD syndrome often affect children.

Some variants in the MLH1 gene cause a form of Lynch syndrome called Muir-Torre syndrome. In addition to colorectal cancer, people with this condition have an increased risk of developing several uncommon skin tumors. These rare skin tumors include sebaceous adenomas and carcinomas, which occur in glands that produce an oily substance called sebum (sebaceous glands). Multiple rapidly growing tumors called keratoacanthomas may also occur, usually on sun-exposed areas of skin.

Ovarian cancer

Inherited changes in the MLH1 gene increase the risk of developing ovarian cancer, as well as other types of cancer, as part of Lynch syndrome (described above). Women with Lynch syndrome have an 8 to 10 percent chance of developing ovarian cancer, as compared with 1.6 percent in the general population.

Other Names for This Gene

• hMLH1
• MLH1_HUMAN
• mutL (E. coli) homolog 1 (colon cancer, nonpolyposis type 2)
• mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli)
• MutL protein homolog 1

Genomic Location

Normal Function

The MSH2 gene provides instructions for making a protein that plays an essential role in repairing DNA. This protein helps fix errors that are made when DNA is copied (DNA replication) in preparation for cell division. The MSH2 protein joins with one of two other proteins, MSH6 or MSH3 (each produced from a different gene), to form a two-protein complex called a dimer. This complex identifies locations on the DNA where errors have been made during DNA replication. Another group of proteins, the MLH1-PMS2 dimer, then binds to the MSH2 dimer and repairs the errors by removing the mismatched DNA and replicating a new segment. The MSH2 gene is one of a set of genes known as the mismatch repair (MMR) genes.

Health Conditions Related to Genetic Changes

Constitutional mismatch repair deficiency syndrome

About 10 variants (also known as mutations) in the MSH2 gene have been associated with a condition called constitutional mismatch repair deficiency (CMMRD) syndrome. Individuals with this condition are at increased risk of developing cancers of the colon (large intestine) and rectum (collectively referred to as colorectal cancer), brain, and blood (leukemia or lymphoma). These cancers usually first occur in childhood, with the vast majority of cancers in CMMRD syndrome diagnosed in people under the age of 18. Many people with CMMRD syndrome also develop changes in skin coloring (pigmentation), similar to those that occur in a condition called neurofibromatosis type 1.

Individuals with CMMRD syndrome inherit two MSH2 gene variants , one from each parent, while people with Lynch syndrome (described below) have a variant in one copy of the MSH2 gene.

MSH2 gene variants result in near or complete loss of MSH2 protein production. A shortage of this protein eliminates mismatch repair activity and prevents the proper repair of DNA replication errors. These errors accumulate as the abnormal cells continue to divide. The errors disrupt other genes involved in important cellular processes, such as controlling cell growth and division (proliferation). If cell growth is uncontrolled, it can lead to childhood cancer in people with CMMRD syndrome.

It is thought that the features of neurofibromatosis type 1 in people with CMMRD syndrome are due to genetic changes in the NF1 gene that result from loss of mismatch repair. These changes are present only in certain cells (somatic variants), whereas NF1 gene variants that are present in all cells of the body cause neurofibromatosis type 1.

Lynch syndrome

About 20 percent of all cases of Lynch syndrome with an identified gene variant are associated with inherited variants in the MSH2 gene. Lynch syndrome increases the risk of many types of cancer, particularly colorectal cancer. People with Lynch syndrome also have an increased risk of cancers of the endometrium (lining of the uterus), ovaries, stomach, small intestine, gallbladder ducts, upper urinary tract, and brain. By age 75, the risk of developing one of these cancers is 80 percent for women and 75 percent for men with an MSH2 gene variant.

MSH2 gene variants involved in Lynch syndrome may cause the production of an abnormally short or inactive MSH2 protein or prevent the production of any protein from one copy of the gene. An altered protein cannot perform its normal function. A decrease in functional MSH2 protein leads to an increase in unrepaired DNA errors during cell division. The errors accumulate as the cells continue to divide, increasing the risk of tumor formation in the colon or another part of the body.

Because there is some functional MSH2 protein produced from the normal copy of the gene, mismatch repair activity in Lynch syndrome is reduced but not absent, as it is in CMMRD syndrome (described above). This difference in DNA repair activity levels likely explains why cancers in Lynch syndrome generally develop in adulthood while those in CMMRD syndrome often affect children.

Some variants in the MSH2 gene cause a form of Lynch syndrome called Muir-Torre syndrome. In addition to colorectal cancer, people with this condition have an increased risk of developing several uncommon skin tumors. These rare skin tumors include sebaceous adenomas and carcinomas, which occur in glands that produce an oily substance called sebum (sebaceous glands). Multiple rapidly growing tumors called keratoacanthomas may also occur, usually on sun-exposed areas of skin.

Ovarian cancer

Inherited changes in the MSH2 gene increase the risk of developing ovarian cancer, as well as other types of cancer, as part of Lynch syndrome (described above). Females with Lynch syndrome have an 8 to 10 percent chance of developing ovarian cancer, as compared with 1.6 percent in the general population.

Other Names for This Gene

• MSH2_HUMAN
• mutS (E. coli) homolog 2
• mutS (E. coli) homolog 2 (colon cancer, nonpolyposis type 1)
• mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli)

Genomic Location

Normal Function

The MSH6 gene provides instructions for making a protein that plays an essential role in repairing DNA. This protein helps fix errors that are made when DNA is copied (DNA replication) in preparation for cell division. The MSH6 protein joins with another protein called MSH2 (produced from the MSH2 gene) to form a two-protein complex called a dimer. This complex identifies locations on the DNA where errors have been made during DNA replication. Additional proteins, including another dimer called the MLH1-PMS2 dimer, then repair the errors by removing the mismatched DNA and replicating a new segment. The MSH6 gene is a member of a set of genes known as the mismatch repair (MMR) genes.

Health Conditions Related to Genetic Changes

Constitutional mismatch repair deficiency syndrome

More than 15 variants (also known as mutations) in the MSH6 gene have been associated with a condition called constitutional mismatch repair deficiency (CMMRD) syndrome. Individuals with this condition are at increased risk of developing cancers of the colon (large intestine) and rectum (collectively referred to as colorectal cancer), brain, and blood (leukemia or lymphoma). These cancers usually first occur in childhood, with the vast majority of cancers in CMMRD syndrome diagnosed in people under the age of 18. Many people with CMMRD syndrome also develop changes in skin coloring (pigmentation), similar to those that occur in a condition called neurofibromatosis type 1.

Individuals with CMMRD syndrome inherit two MSH6 gene variants, one from each parent, while people with Lynch syndrome (described below) have a variant in one copy of the MSH6 gene.

MSH6 gene variants result in near or complete loss of MSH6 protein production. A shortage of this protein eliminates mismatch repair activity and prevents the proper repair of DNA replication errors. These errors accumulate as the abnormal cells continue to divide. The errors disrupt other genes involved in important cellular processes, such as controlling cell growth and division (proliferation). If cell growth is uncontrolled, it can lead to childhood cancer in people with CMMRD syndrome.

It is thought that the features of neurofibromatosis type 1 in people with CMMRD syndrome are due to genetic changes in the NF1 gene that result from loss of mismatch repair. These changes are present only in certain cells (somatic variants), whereas NF1 gene variants that are present in all cells of the body cause neurofibromatosis type 1.

Lynch syndrome

Variants in the MSH6 gene have been reported in about 13 percent of families with Lynch syndrome that have an identified gene variant. Lynch syndrome increases the risk of many types of cancer, particularly colorectal cancer. People with Lynch syndrome also have an increased risk of cancers of the endometrium (lining of the uterus), ovaries, stomach, small intestine, gallbladder ducts, upper urinary tract, and brain. By age 75, the risk of developing one of these cancers is 60 percent for women and 40 percent for men with an MSH6 gene variant. Endometrial cancer is especially common in women with Lynch syndrome caused by MSH6 gene variants.

MSH6 gene variants involved in this condition lead to the production of an abnormally short, nonfunctional MSH6 protein; a partially active version of the protein; or no protein product from one copy of the gene. A decrease in functional MSH6 protein leads to an increase in unrepaired DNA errors during cell division. The errors accumulate as the cells continue to divide, which may cause the cells to function abnormally, increasing the risk of tumor formation in the colon or another part of the body.

Because there is some functional MSH6 protein produced from the normal copy of the gene, mismatch repair activity in Lynch syndrome is reduced but not absent, as it is in CMMRD syndrome (described above). This difference in DNA repair activity levels likely explains why cancers in Lynch syndrome generally develop in adulthood while those in CMMRD syndrome often affect children.

In a small number of people, variants in the MSH6 gene cause a form of Lynch syndrome called Muir-Torre syndrome. In addition to colorectal cancer, people with this condition have an increased risk of developing several uncommon skin tumors. These rare skin tumors include sebaceous adenomas and carcinomas, which occur in glands that produce an oily substance called sebum (sebaceous glands). Multiple rapidly growing tumors called keratoacanthomas may also occur, usually on sun-exposed areas of skin.

Ovarian cancer

MedlinePlus Genetics provides information about Ovarian cancer

Other Names for This Gene

• G-T binding protein
• G/T mismatch-binding protein
• GTBP
• mutS (E. coli) homolog 6
• mutS homolog 6 (E. coli)
• MutS-alpha 160 kDa subunit

Genomic Location

Normal Function

The PMS2 gene provides instructions for making a protein that plays an essential role in repairing DNA. This protein helps fix errors that are made when DNA is copied (DNA replication) in preparation for cell division. The PMS2 protein joins with another protein called MLH1 (produced from the MLH1 gene) to form a two-protein complex called a dimer. This complex coordinates the activities of other proteins that repair errors made during DNA replication. Repairs are made by removing the section of DNA that contains errors and replacing it with a corrected DNA sequence. The PMS2 gene is a member of a set of genes known as the mismatch repair (MMR) genes.

Health Conditions Related to Genetic Changes

Constitutional mismatch repair deficiency syndrome

More than 55 variants (also known as mutations) in the PMS2 gene have been associated with a condition called constitutional mismatch repair deficiency (CMMRD) syndrome. PMS2 gene variants are the most frequent cause of this condition. Individuals with CMMRD syndrome are at increased risk of developing cancers of the colon (large intestine) and rectum (collectively referred to as colorectal cancer), brain, and blood (leukemia or lymphoma). These cancers usually first occur in childhood, with the vast majority of cancers in CMMRD syndrome diagnosed in people under the age of 18. Many people with CMMRD syndrome also develop changes in skin coloring (pigmentation), similar to those that occur in a condition called neurofibromatosis type 1.

Individuals with CMMRD syndrome inherit two PMS2 gene variants, one from each parent, while people with Lynch syndrome (described below) have a variant in one copy of the PMS2 gene.

PMS2 gene variants result in near or complete loss of PMS2 protein production. A shortage of this protein eliminates mismatch repair activity and prevents the proper repair of DNA replication errors. These errors accumulate as the abnormal cells continue to divide. The errors disrupt other genes involved in important cellular processes, such as controlling cell growth and division (proliferation). If cell growth is uncontrolled, it can lead to childhood cancer in people with CMMRD syndrome.

It is thought that the features of neurofibromatosis type 1 in people with CMMRD syndrome are due to genetic changes in the NF1 gene that result from loss of mismatch repair. These changes are present only in certain cells (somatic variants), whereas NF1 gene variants that are present in all cells of the body cause neurofibromatosis type 1.

Lynch syndrome

Variants in the PMS2 gene have been reported in about 6 percent of families with Lynch syndrome that have an identified gene alteration. Lynch syndrome increases the risk of many types of cancer, particularly colorectal cancer. People with Lynch syndrome also have an increased risk of cancers of the endometrium (lining of the uterus), ovaries, stomach, small intestine, liver, gallbladder ducts, upper urinary tract, and brain. By age 75, the risk of developing one of these cancers is 30 percent for women and 25 percent for men with a PMS2 gene variant. These variants lead to a form of Lynch syndrome with a lower risk of cancer development compared to other causes of this condition. Additionally, in people with a PMS2 gene variant, cancer tends to occur at a later age compared to others with Lynch syndrome. The reason for this lower cancer risk is unclear.

PMS2 gene variants involved in this condition lead to the production of an abnormally short or inactive PMS2 protein from one copy of the gene. The altered protein cannot efficiently repair errors made during DNA replication. The errors accumulate as the cells continue to divide, increasing the risk of tumor formation in the colon or another part of the body.

Because there is some functional PMS2 protein produced from the normal copy of the gene, mismatch repair activity in Lynch syndrome is reduced but not absent, as it is in CMMRD syndrome (described above). This difference in DNA repair activity levels likely explains why cancers in Lynch syndrome generally develop in adulthood while those in CMMRD syndrome often affect children.

Alopecia areata

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Ovarian cancer

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Other Names for This Gene

• PMS2 postmeiotic segregation increased 2 (S. cerevisiae)
• PMS2_HUMAN
• postmeiotic segregation increased (S. cerevisiae) 2

Genomic Location

Normal Function

The EPCAM gene provides instructions for making a protein known as epithelial cellular adhesion molecule (EpCAM). This protein is found in epithelial cells, which are the cells that line the surfaces and cavities of the body. The EpCAM protein is found spanning the membrane that surrounds epithelial cells, where it helps cells stick to one another (cell adhesion). In addition, the protein in the cell membrane can be cut at a specific location, releasing a piece called the intracellular domain (EpICD), which helps relay signals from outside the cell to the nucleus of the cell. EpICD travels to the nucleus and joins with other proteins, forming a group (complex) that regulates the activity of several genes that are involved in many cell processes, including growth and division (proliferation), maturation (differentiation), and movement (migration), all of which are important processes for the proper development of cells and tissues.

Health Conditions Related to Genetic Changes

Lynch syndrome

Certain variants (also known as mutations) in the EPCAM gene are associated with Lynch syndrome, a condition that increases the risk of developing many types of cancer, particularly cancers of the large intestine (colon) and the rectum (collectively called colorectal cancer). These variants account for up to 3 percent of Lynch syndrome cases. On chromosome 2, the EPCAM gene lies next to another gene called MSH2. Each gene provides instructions for making an individual messenger RNA (mRNA), which serves as the genetic blueprint for making the protein. The EPCAM gene variants involved in Lynch syndrome remove a region that signals the end of the gene, which leads to formation of a long mRNA that includes both EPCAM and MSH2.

For unknown reasons, these EPCAM gene variants cause the MSH2 gene to be turned off (inactivated) by a mechanism known as promoter hypermethylation. The promoter is a region of DNA near the beginning of the gene that controls gene activity (expression). Hypermethylation occurs when too many small molecules called methyl groups are attached to the promoter region. The extra methyl groups attached to the MSH2 promoter reduce the expression of the MSH2 gene, which means that less protein is produced in epithelial cells.

The MSH2 protein plays an essential role in repairing errors in DNA; loss of this protein prevents proper DNA repair, and errors accumulate as the cells continue to divide. These errors can lead to uncontrolled cell growth and increase the risk of cancer.

Other disorders

Variants in the EPCAM gene can also cause congenital tufting enteropathy. This condition is characterized by abnormal development of epithelial cells in the intestines. In this condition, the villi, which are small finger-like projections that line the small intestine, are abnormal. In particular, they have "tufts" of extra epithelial cells on their tips. Normally, these projections provide a greatly increased surface area to absorb nutrients. The altered villi are less able to absorb nutrients and fluids than normal tissue, which causes life-threatening diarrhea and poor growth. Congenital tufting enteropathy develops in newborns within days of birth and lasts throughout life.

People with congenital tufting enteropathy have two copies of the altered EPCAM gene in each cell. These variants lead to an absence of functional EpCAM protein. The resulting loss of EpICD signaling leads to abnormal development of intestinal epithelial cells, causing congenital tufting enteropathy.

Other Names for This Gene

• EGP-2
• EGP34
• EGP40
• Ep-CAM
• epithelial cell adhesion molecule precursor
• epithelial glycoprotein 314
• human epithelial glycoprotein-2
• TACST-1
• TACSTD1
• TROP1
• tumor-associated calcium signal transducer 1

Genomic Location

Having a family health history of Lynch syndrome makes you more likely to have Lynch syndrome yourself. Lynch syndrome is an inherited genetic condition that makes you more likely to get colorectal (colon) and other types of cancer.

If someone in your family has been diagnosed with Lynch syndrome, share this information with your doctor. Your doctor may refer you for genetic counseling or genetic testing. If you have Lynch syndrome, let your family members know. Note that not all inherited colorectal cancers are due to Lynch syndrome, and not everyone with Lynch syndrome will get colorectal cancer.

Lynch syndrome is hereditary, meaning that it is caused by an inherited genetic change, or mutation, that can be passed from parent to child. If you have Lynch syndrome, your parents, children, sisters, and brothers have a 50% chance of having Lynch syndrome. Once a mutation that causes Lynch syndrome is found in one person in a family, other members can then be tested for that mutation to find out if they have Lynch syndrome.

Tell your doctor if you have

• A first-degree relative (parents, sisters, brothers, and children) with Lynch syndrome
• A first-degree relative with colorectal or endometrial cancer diagnosed before age 50
• A first-degree relative with colorectal or endometrial cancer and another Lynch syndrome related cancer either occurring at the same time, or at a different time.
• Two or more first- or second-degree relatives (grandparents, aunts, uncles, and half-siblings) with Lynch syndrome related cancers, and at least one that was diagnosed before age 50
• Three or more first- or second-degree relatives with Lynch syndrome-related cancers at any age

If you have a family history of Lynch syndrome, your doctor may recommend genetic counseling.

Genetic testing is available for Lynch syndrome. However, most colorectal cancer is not caused by inherited mutations, so Lynch syndrome testing will not benefit most people with a family health history of colorectal cancer who have not had cancer themselves. Genetic testing will not identify the cause for some hereditary colorectal cancers, because the genes affected in these cancers are not yet known.

Usually, genetic testing will be recommended if

• Your tumor screening results (IHC or MSI) are abnormal
• You have had colorectal cancer
• You had uterine (endometrial cancer) before age 50
• You have had multiple primary cancer diagnoses
• Several family members have had cancers related to Lynch syndrome
• You have a family member with Lynch syndrome

Genetic testing looks for inherited Lynch syndrome mutations. Your doctor may recommend a multi-gene panel, which looks for mutations in several genes at the same time, including the genes associated with Lynch syndrome.

The genetic counselor can help to determine the best testing strategy for you and your family. When possible, testing should start with someone in the family who has had cancer. However, if none of your family members who have had cancer are available for testing, genetic testing can start with an unaffected person.

Genetic Testing Results

Interpretation of genetic testing results may vary, depending on whether you have had colorectal cancer in the past or not.

If you have already colorectal cancer what the test results mean to you and your family

You have not had colorectal cancer what the test results mean to you and your family

When a person is diagnosed with colorectal cancer, their tumor tissue is often screened to see if their cancer was caused by Lynch syndrome. In some cases, when a woman is diagnosed with uterine (endometrial) cancer, her tumor tissue may be screened as well. The tumor tissue used for screening comes from tissue removed during a biopsy or surgery.

There are two types of Lynch syndrome tumor screening: Immunohistochemistry (IHC) and microsatellite instability (MSI) testing.

Not everyone with an abnormal IHC or MSI result will have Lynch syndrome, and additional testing may be necessary if a tumor screens positive. Genetic counseling and genetic testing for Lynch syndrome may be recommended if your tumor screening results are abnormal. If you are unsure whether or not your tumor has been checked for Lynch syndrome, talk to your doctor.

IHC screening looks to see if certain proteins are absent in the tumor sample, indicating that one of the Lynch syndrome genes might not be working properly. Lynch syndrome mutations affect whether the MLHL, MSH2, MSH6, and PMS2 proteins are made and located in the correct place.

Test Results, their meaning and the next Steps

MSI screening is used to see if the Lynch syndrome genes are working properly. Microsatellites are regions of repeated DNA that change in length (show instability) when mismatch repair is not working properly. MSI testing looks at the length of certain DNA microsatellites from the tumor sample to see if they have gotten longer or shorter as a measure of instability.

Test Results, their meaning and the next Steps

Several medical options are available for managing cancer risks in people who have Lynch syndrome. These options all have risks and benefits, and should be discussed with a doctor before making any medical decisions.

Colonoscopies every 1-2 years starting between the ages of 20-25 (or 2-5 years before the earliest colorectal cancer in the family) are the most effective way to prevent colorectal cancer.

Other available options may reduce the chance of developing cancer or improve the likelihood of detecting it earlier, but the effectiveness of these options is less certain and should be discussed with a doctor:

• Daily aspirin use to reduce the risk of colorectal cancer
• Transvaginal ultrasound and endometrial biopsy every 1–2 years, beginning at age 30–35 years, to detect endometrial cancer
• CA-125 blood tests every year to detect ovarian cancer
• Hysterectomy and bilateral salpingo-oophorectomy to prevent gynecologic cancers
• Upper endoscopies every 3-5 years starting between the ages of 30-35 to detect stomach and small bowel cancer
• Urinalysis every year starting between the ages of 30-35 to detect bladder cancer
• Physical and neurological exams starting between the ages of 25-30 every year to check for cancer in the central nervous system

Knowing the Symptoms of Gynecologic Cancers Saves Lives

If you are a woman with Lynch syndrome, you are more likely to get uterine (endometrial) and ovarian cancer. Talk to your doctor if you experience symptoms of gynecologic cancers including

• Abnormal vaginal bleeding, especially if you are past menopause,
• Pain or pressure in the pelvic area,
• Abdominal or back pain,
• Bloating,
• Feeling full too quickly or difficulty eating, or
• A change in your bathroom habits, such as more frequent or urgent need to urinate or constipation.