What is Lynch syndrome? Colon cancer genes, risks and genetic testing

Sometimes, but usually not. Most colon cancers happen by chance.^[15] About 5% of people who develop colorectal (colon) cancer have an inherited gene change that causes a family cancer syndrome, the American Cancer Society says. The most common are Lynch syndrome and familial adenomatous polyposis (FAP).^[16]

Family history matters on its own, too. As many as 1 in 3 people who develop colorectal cancer have family members who had it. Your risk is higher if a parent, brother, sister or child has had colorectal cancer, and higher still if they were diagnosed before 50 or if more than one of them has had it. Cancer can run in a family because of inherited genes, a shared environment, or both, and the reason isn’t always clear.^[16]

It can come from either one. Lynch syndrome and FAP are what doctors call autosomal dominant: the gene isn’t on the X or Y chromosome, so either parent can pass it on, and one changed copy is enough to cause the condition.^[22][1][21] A parent who has one of these conditions has a 50% chance of passing it to each child.^[21][13] So when you share your family’s cancer history with your doctor, as CDC suggests, include both your mother’s side and your father’s.^[15] One syndrome described below, MUTYH-associated polyposis, works differently: you need a changed copy from each parent to have it.^[10]

It can. Cancer in a close relative, such as a parent, brother or sister, is the most concerning, but cancer in more distant relatives can also be important, the American Cancer Society says. Grandparents, aunts and uncles are among those more distant, second-degree relatives. Having two or more relatives with colorectal cancer is more concerning than having one, and so is a diagnosis at a younger age than usual. A doctor may also suspect Lynch syndrome when colorectal cancer and other cancers linked to it turn up among your relatives.^[17] Endometrial (womb) cancer is one of those.^[1]

If your family fits any of the signs CDC lists under who should ask about testing, talk to a clinician or genetic counselor. The American Cancer Society says people at increased or high risk might need to start screening before 45, be screened more often or have specific tests, and that these guidelines are best reviewed with your healthcare provider.^[18]

No. A stool DNA test is a colorectal cancer screening test: it looks for abnormal DNA from cancer or polyp cells in your stool, plus hidden blood.^[19] A genetic test for inherited risk reads the DNA you were born with, your germline DNA, for changes that can run in families.^[23]

One doesn’t replace the other. The US Preventive Services Task Force’s screening recommendation, stool DNA tests included, is for adults at average risk. That leaves out people who have, or have a family history of, an inherited condition such as Lynch syndrome or FAP.^[20] And not every genetic test reads whole genes, which is why an at-home test can’t rule Lynch syndrome out.

Lynch syndrome is an inherited condition that raises the risk of many types of cancer. They include colorectal (colon) cancer and, in women, endometrial and ovarian cancer, as well as cancers of the stomach, small intestine, liver, gallbladder ducts, urinary tract, brain and skin.^[1]

It is caused by a variant in one of four mismatch repair genes, MLH1, MSH2, MSH6 or PMS2, or by certain variants in a fifth gene, EPCAM, that switch MSH2 off. Mismatch repair genes help fix the errors that happen when DNA is copied before a cell divides.^[1]

One altered copy of the gene is enough to raise the risk of cancer. Even so, not everyone with Lynch syndrome develops cancer.^[1]

About 1 in 279 people carry a variant linked with Lynch syndrome. That estimate comes from a study of the families of 5,744 people with colorectal cancer in the United States, Canada and Australia.^[3][1]

EPCAM variants are a small share. They remove the region that marks the end of the EPCAM gene, which turns MSH2 off, and they account for up to 3% of Lynch syndrome.^[2]

Risks differ a lot from one gene to another. An international study that followed 3,119 carriers over time, the Prospective Lynch Syndrome Database, estimated these risks by age 75:^[4]

PMS2 carriers had lower risks.^[4] A later analysis of 6,350 carriers found no significant rise in cancer risk for PMS2 carriers, and only a modest rise in colorectal cancer risk for MSH6 carriers, whose main risk was endometrial cancer.^[5]

Guidelines describe earlier and more frequent screening for people with Lynch syndrome. What follows is a description, not a plan. Your clinician sets yours.

• Colonoscopy. CDC describes colonoscopy every 1 to 2 years, starting 2 to 5 years before the earliest colorectal cancer diagnosed in your family.^[9]
• The womb and ovaries. Options CDC lists include transvaginal ultrasound and biopsy, CA-125 blood tests, and surgery to remove the uterus, ovaries and fallopian tubes.^[9]
• Other cancers. CDC notes there are no routine screening tests for the other cancers linked with Lynch syndrome, and suggests talking to your doctor about the best ways to manage your risk.^[9]

The case for colonoscopy has a long history. The National Cancer Institute (NCI) notes that colonoscopy every 1 to 2 years, and in one study up to 3 years, has been shown to reduce colorectal cancer cases and deaths in people with Lynch syndrome.^[10] In a 15-year Finnish trial in families with the condition, colonoscopy every 3 years cut colorectal cancer by 62%, and there were no colorectal cancer deaths in the screened group, against 9 in the group that wasn’t screened.^[11]

CDC says genetic testing for Lynch syndrome is usually recommended if:^[12]

• tumor testing of your cancer showed an abnormal result;
• you have had colorectal cancer;
• you had uterine (endometrial) cancer before age 50;
• you have had several types of cancer;
• several members of your family have had cancers related to Lynch syndrome; or
• a member of your family has Lynch syndrome.

CDC also says genetic counseling before testing is important, to find out whether you and your family are likely to benefit from it.^[12]

Lynch syndrome is one of several inherited cancer syndromes. For the others, and the routes to a test, read our guide to genetic testing for cancer.

If you have Lynch syndrome, each of your parents, brothers and sisters, and children has a 50% chance of having it too. Aunts, uncles, nieces, nephews and cousins are also more likely to have it.^[13]

Relatives who get genetic testing should be tested for the same genetic change you have.^[12] Sharing the details of your exact variant makes that possible. This is called cascade testing.

Familial adenomatous polyposis (FAP) and Lynch syndrome are the two most common inherited syndromes linked with colorectal cancer.^[16] Because FAP causes polyps and cancer earlier than the age routine colon screening usually starts, it sometimes isn’t found until someone already has cancer.^[17]

Genetic testing for FAP. Genetic counseling and testing are available for people who may have FAP because of their personal or family history. A doctor may also suspect FAP when a colonoscopy finds many polyps. When the gene change is found in one person, doctors recommend testing their brothers, sisters and children.^[17]

NCI describes two broad forms of inherited colorectal cancer: Lynch syndrome, and the polyposis syndromes, where the bowel grows many polyps.^[10] Three polyposis syndromes are below. This is background about genes and cancers, not a list of what any one test checks.

• Familial adenomatous polyposis (FAP). Caused by variants in APC. In its classic form, hundreds to thousands of polyps grow in the colon and rectum, starting after about age 10.^[10]
• MUTYH-associated polyposis. Caused by variants in MUTYH. Unlike Lynch syndrome, it is recessive: a person has it only when both copies of the gene carry a variant, one from each parent.^[10]
• Juvenile polyposis syndrome. A rare condition linked to SMAD4 and BMPR1A, in which a particular kind of polyp, called a juvenile polyp, grows in the colon or rectum and sometimes elsewhere in the digestive tract.^[10]

A result with no variant found can’t rule out inherited cancer risk.

Each has its own pattern in a family, and a clinician who suspects one chooses the genes to test from that pattern.

No. A test of selected variants checks only the variants on its list. Lynch syndrome can come from variants in any of five genes, including deletions, which a test of single positions may not detect.^[2] And in a large study of genotyping chips, the chips missed most of the rare harmful variants in the genes the study examined.^[14] So a result with no variant found can’t rule Lynch syndrome out.

If any of the signs above apply to you, or you have had cancer, the right route is clinician-ordered genetic testing that reads the genes in full and looks for missing pieces, and tumor testing where there is a cancer. At-home or clinical testing? explains the difference.

Checks selected variants across 108 genes, including BRCA1 and BRCA2, by genotyping. Which variants it checks in each of its genes isn’t published yet, so we don’t say which Lynch syndrome variants it covers. It reads selected variants, not the genes in full, and Lynch syndrome can come from many different variants, deletions among them. So a result with none found can’t rule Lynch syndrome out, and it isn’t a substitute for tumor testing or clinician-ordered genetic testing.

Selected variants only, by genotyping. Not a full-gene test.

GeneCancer is for people without a personal or family history of cancer. If it finds a variant, ask your clinician to confirm it with a clinical test before any decision.

• Whether you have cancer now. A genetic result isn’t a diagnosis. If you have symptoms, see your doctor.
• That you don’t have Lynch syndrome, if it came from a test of selected variants.
• Exactly what will happen. Risk estimates describe groups of carriers, and not everyone with Lynch syndrome develops cancer.^[1]
• Your screening plan. Your clinician sets it, from your gene, your age and your family history.