Familial adenomatous polyposis (APC) and MUTYH-associated polyposis

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Familial adenomatous polyposis and MUTYH-associated polyposis are inherited conditions that cause large numbers of precancerous growths, called adenomas, to develop in the colon and rectum. Left alone, some of those adenomas become cancer. Familial adenomatous polyposis, usually shortened to FAP, is caused by a change in the APC gene. MUTYH-associated polyposis, shortened to MAP, is caused by changes in the MUTYH gene.

The two are covered together because they produce a similar picture in the colon and are often distinguished only by genetic testing. They differ in one fundamental respect: they are inherited in different ways. FAP requires a single altered copy of APC, so it passes directly from an affected parent to half their children. MAP requires an altered copy of MUTYH from both parents, which means it can appear in a family with no previous history at all. This difference changes what a result means for relatives, and it is explained in detail below.

These conditions differ from most hereditary cancer syndromes in a way that matters for how they are managed. Cancer here does not arise unpredictably from apparently normal tissue. It arises from adenomas that can be seen, counted, and removed. That makes these among the most preventable of all inherited cancer risks, and it is why surveillance and surgical timing dominate the discussion.

This article is written both for people diagnosed with polyposis or a related cancer and for people who carry a gene change without having had cancer, including young people identified through family testing.

What do the APC and MUTYH genes do?

APC is a tumor suppressor gene that restrains the growth of cells lining the colon. When it stops working in a cell, that cell begins to multiply without the usual brake, forming an adenoma. This is the first step in the development of most colorectal cancers, including those with no inherited cause. A person with FAP is born with one non-working copy of APC in every cell of the colon, so this first step has already been taken everywhere. Adenomas therefore form in enormous numbers rather than one at a time.

MUTYH works differently. It repairs a specific kind of DNA damage caused by oxygen, one of the most common forms of wear a cell sustains. A person with two non-working copies cannot make this repair, so errors accumulate steadily. Those errors land in many genes, and one of the genes most often hit is APC. The end result resembles FAP, by a different route.

Understanding this explains a practical point. In FAP, the gene change is present in every cell from birth, and the polyps start early, often in the teens. In MAP the errors take time to accumulate, so polyps and cancer generally appear later, around middle age.

Cancers and other findings associated with these conditions

Colorectal cancer

In classic FAP, hundreds to thousands of adenomas develop in the colon and rectum, usually beginning in the teenage years. Most are tubular adenomas, though tubulovillous and villous adenomas also occur, and the larger ones carry the greater risk. Without treatment, colorectal cancer is close to inevitable, with an average age at diagnosis around 39. Cancer often begins within one of the adenomas rather than in flat lining. This near-certainty is the reason preventive removal of the colon is standard rather than optional.

In attenuated FAP, a milder form caused by changes in particular parts of the APC gene, the number of adenomas is far smaller, often around 30, they tend to sit further up the colon, and cancer arrives later. Lifetime risk of colorectal cancer is around 70%, still far above the general population figure of about 4%, and management is correspondingly less intensive.

In MAP, most people develop somewhere between 10 and a few hundred adenomas, with an average age at diagnosis around 45. Lifetime risk of colorectal cancer without surveillance is high, with estimates ranging from around 43% to over 80% by age 60. A meaningful minority of people with MAP develop colorectal cancer with few or no polyps at all, which is one reason the diagnosis is sometimes missed.

Cancer of the duodenum and stomach

Because preventive colon surgery has largely removed colorectal cancer as a cause of death in FAP, cancer of the duodenum, the first part of the small bowel, has become the leading cancer-related cause of death in this condition. Duodenal adenomas develop in most people with FAP over time, and lifetime risk of cancer of the small intestine at this site is in the range of 3% to 12%, compared with well under 1% in the general population. Adenomas around the ampulla, where the bile duct enters the bowel, carry the highest risk, and cancer arising there is called ampullary adenocarcinoma.

Non-cancerous stomach polyps called fundic gland polyps are very common in FAP and are usually harmless. Stomach cancer risk is low in most populations. People with MAP also develop duodenal adenomas, in roughly 17% to 25% of cases, though less often than in FAP.

Desmoid tumors

Desmoid tumors, also called desmoid fibromatosis, occur in around 10% to 15% of people with FAP and are a leading cause of serious illness after colon surgery. They are growths of fibrous tissue that do not spread to other parts of the body but grow into surrounding structures, most often in the abdomen. They frequently appear after abdominal surgery, which is one factor weighed when planning the timing and type of colon operation. They are uncommon in MAP.

Other findings

Thyroid cancer — Papillary thyroid carcinoma occurs more often in FAP, particularly in young women, which is why annual thyroid examination is part of care. One uncommon type, cribriform-morular thyroid carcinoma, is so closely linked to FAP that a diagnosis of it prompts testing even with no other findings.
Hepatoblastoma — A rare liver cancer of early childhood, occurring in under 2% of children with FAP, and the reason blood tests and liver ultrasound are offered in the first few years of life in some centers.
Brain tumors — Uncommon, but the combination of polyposis and a brain tumor has historically been called Turcot syndrome.
Non-cancerous features — Benign bone growths called osteomas, extra or unerupted teeth, skin cysts including epidermoid cysts, and a harmless pigmented patch at the back of the eye. These are not dangerous, but they sometimes lead to the diagnosis, since a dentist or optometrist may notice them first.

How lifetime risk is estimated and why the numbers vary

Risk figures for these conditions are quoted with more confidence than for most hereditary cancer syndromes, because the mechanism is visible. Anyone can count polyps at colonoscopy, so the relationship between the gene change and the disease is far less speculative than for syndromes where cancer arises unpredictably.

The variation that does exist comes from three sources:

Where in the APC gene the change sits — This determines whether a person has classic or attenuated FAP, and the difference between hundreds of polyps in the teens and thirty polyps in middle age is substantial. Changes in the middle of the gene produce the most florid disease.
Whether the figures describe treated or untreated disease — The frequently quoted “close to 100% risk of colorectal cancer” in classic FAP describes what happens without surgery. It does not describe what happens to someone under surveillance who has their colon removed at the appropriate time. In modern practice, most people with FAP do not develop colorectal cancer.
How the person came to be tested — As with all these conditions, families identified because of severe disease produce higher estimates than people found incidentally on a panel.

An important consequence follows from the second point. Unlike most of the risk figures in this section, the headline number for FAP describes a natural course that modern care is designed to prevent. Someone reading that colorectal cancer is inevitable is reading about untreated disease.

Who should be tested?

Genetic testing is generally offered when:

Ten or more adenomas have been found in a person’s lifetime, which is the usual threshold for investigating a polyposis syndrome. Twenty or more makes an inherited cause considerably more likely.
A parent, sibling, or child has FAP or MAP, or a gene change has already been identified in the family.
Colorectal cancer occurs at a young age alongside multiple adenomas.
Characteristic non-colonic findings are present, such as a desmoid tumor, multiple osteomas, or hepatoblastoma in a child.

Testing usually examines both genes together, since the two conditions cannot reliably be distinguished by the appearance of the colon alone.

Two situations complicate the picture. Roughly a quarter of people with classic FAP have a new gene change rather than an inherited one, so there is no family history to notice. And some people carry an APC change in only a proportion of their cells, a situation called mosaicism, which can produce polyposis while a standard blood test appears normal. Where the colon shows clear polyposis but blood testing is negative, testing of polyp tissue itself may resolve it.

How the test is performed

Germline testing is done on a blood or saliva sample and examines the DNA a person was born with. The analysis uses next generation sequencing together with a method that detects large deletions and duplications, since a proportion of APC changes are large rearrangements that sequencing alone will not find.

For MUTYH, the laboratory reports how many copies of the gene are affected, and this distinction is the single most important part of the result. Biallelic means both copies carry a change, and the person has MUTYH-associated polyposis. Monoallelic or heterozygous means only one copy is affected, and the person is a carrier rather than affected. Your report should state which, and if it does not, ask.

How results are reported

Pathogenic or likely pathogenic variant — A change known, or strongly expected, to stop the gene working. For APC this confirms FAP. For MUTYH, the number of affected copies determines what it means.
Variant of uncertain significance — A change was found but its effect is unknown. This is not a positive result. It is managed as though negative, with surveillance guided by the appearance of the colon and by family history, and it is never a basis for removing the colon. Our article on variants of uncertain significance explains this result in detail.
Benign or likely benign variant — A harmless difference, usually not reported.
No variant identified — No change was found in the genes tested.

What the result means

A pathogenic APC variant confirms FAP. Where in the gene it sits gives some indication of whether the classic or attenuated form is likely. Each child, sibling, and parent has a 50% chance of carrying the same change.

Two pathogenic MUTYH variants confirm MAP. The implications for relatives are quite different from FAP and are explained below.

One pathogenic MUTYH variant means the person is a carrier. Carriers do not have MAP. Whether a single MUTYH change raises colorectal cancer risk at all has been debated for years. Some studies have suggested a modest increase, roughly twofold, while a more recent study of carriers found no excess of adenomas or cancers. Current guidance in most centers is that carriers with no family history follow the same colorectal screening as the general population, and that those with an affected first-degree relative may be offered earlier or more frequent colonoscopy. The main significance of a carrier result is for family planning.

A negative result means two different things:

True negative — A specific change is already known in your family and you tested negative for that exact change. Your risk returns to that of the general population and routine screening applies.
Uninformative negative — No change has been identified in anyone in the family. If polyps are present, the polyposis is real regardless of what the test showed, and surveillance continues based on what the colon looks like. A proportion of people with clear polyposis have no identifiable gene change.

Germline versus somatic APC changes

A germline change is present in the DNA a person was born with, exists in every cell, and can be passed to children. That is what causes these conditions.

A somatic change arises within a tumor during life, exists only in the tumor cells, and cannot be inherited.

This distinction matters particularly for APC, because somatic APC changes are found in the great majority of ordinary colorectal cancers and adenomas. Loss of APC is the usual first step in colorectal cancer whether or not anything was inherited. A pathology report or tumor sequencing panel describing an APC mutation in a colorectal cancer is therefore an expected finding and does not suggest FAP. What suggests FAP is the number of adenomas in the colon, not the presence of an APC change in one tumor.

Surveillance and risk reduction

Colonoscopy

Surveillance begins earlier in these conditions than in almost any other condition because the adenomas do.

Classic FAP — Colonoscopy or flexible sigmoidoscopy every one to two years beginning at age 10 to 15.
Attenuated FAP — Beginning in late adolescence, generally every one to two years.
MAP — Beginning around age 25 to 30, every one to two years.

The purpose of surveillance changes over time. Early on, it establishes how many polyps are developing and how fast. Later it informs the decision about when surgery is needed. In attenuated FAP and MAP, where numbers are smaller, colonoscopy with removal of polyps can sometimes keep the colon under control for many years without surgery.

Surgery to remove the colon

For classic FAP, removing the colon is not one option among several. The number of adenomas eventually exceeds what can be managed endoscopically, and cancer becomes close to certain without surgery. The questions are when and which operation, not whether.

Timing is usually in the late teens or early twenties, though it is individualized. It is generally planned to allow a young person to finish school and to be old enough to participate in the decision, and it is brought forward if polyps are numerous, large, or show high grade dysplasia.

The operation depends mostly on how many polyps are in the rectum. Removing the colon while leaving the rectum in place, with the small bowel joined to the rectum, preserves better bowel function but leaves rectal tissue that requires lifelong endoscopic surveillance and can still develop cancer. Removing the colon and rectum together, with a pouch constructed from small bowel, removes almost all the at-risk tissue but generally results in more frequent and looser bowel movements. Neither is universally correct. The balance depends on the polyp burden, on the specific gene change, on the risk of desmoid tumors, and on what the person is willing to live with.

For attenuated FAP and MAP, surgery is considered when polyps can no longer be controlled at colonoscopy, which for some people never happens.

Upper endoscopy

Examination of the stomach and duodenum generally begins at age 20 to 25, or before colon surgery if that comes earlier. The endoscopist specifically examines the ampulla, using a side-viewing scope. Findings are graded using a scoring system based on the number and size of polyps and their appearance under the microscope, and that score sets the interval for the next examination, which may range from every few years to annually. Polyps can often be removed endoscopically, and surgery on the duodenum is reserved for advanced disease.

Other surveillance

Thyroid — Annual examination, often with ultrasound, from the late teens.
Desmoid tumors — Abdominal examination annually, with imaging if symptoms develop or a mass is felt.
Liver in young children — Blood tests and ultrasound every few months until around age five in some centers, to detect hepatoblastoma.

Medication

Anti-inflammatory medications reduce polyp numbers in these conditions, and several have been studied. None replaces surgery or surveillance, and their role is limited. This is an active area of research, and your team can tell you whether any trial applies to your situation.

Testing family members

This is where the two conditions diverge most sharply, and confusing them causes real problems.

FAP

APC-related FAP is inherited in an autosomal dominant pattern. A single altered copy causes the condition, and each child, sibling, and parent of an affected person has a 50% chance of carrying the same change. It passes through fathers and mothers equally.

Children of an affected parent are tested in childhood, generally around age 10 to 12. This differs from most hereditary cancer syndromes, where testing is deferred to adulthood, and the reason is straightforward: surveillance colonoscopy starts at 10 to 15, so a child who has not been tested would either undergo unnecessary procedures or miss necessary ones. A child who tests negative is spared a decade of colonoscopies. Genetics services and pediatric teams are experienced at supporting families through this.

Where the gene change arose new in a person, their parents and siblings are usually unaffected, though testing may still be offered because of the possibility of mosaicism.

MAP

MAP is inherited in an autosomal recessive pattern, and this changes everything about what a diagnosis means for a family.

A person with MAP inherited one altered MUTYH copy from each parent. Both parents are therefore carriers, and are almost always healthy. Each sibling has a 25% chance of having MAP, a 50% chance of being a carrier, and a 25% chance of neither. Siblings are the priority for testing.

Children of a person with MAP are usually not affected. Every child inherits one altered copy from the affected parent, but they would need a second altered copy from the other parent to develop the condition. Since roughly 1 in 45 people carries a MUTYH change, this is uncommon. Testing the unaffected partner is the efficient way to establish whether the children are at risk, and if that partner is not a carrier, the children will all be carriers but will not have MAP.

This pattern also explains why MAP frequently appears in families with no history of colorectal cancer at all. A recessive condition can pass silently through generations of carriers before two of them have a child together.

What happens next

For someone newly diagnosed with polyposis, the sequence is genetic testing to establish which condition is present, a full assessment of the colon and upper gastrointestinal tract, and a discussion about surgical timing. Referral to a specialist polyposis registry or hereditary gastrointestinal cancer center is standard, since these conditions require decades of coordinated care.

For a carrier identified through family testing, the work is establishing a surveillance schedule appropriate to the condition and the age at which it starts.

Living with these conditions involves more medical contact over a lifetime than most, beginning in adolescence and continuing indefinitely. Many centers have dedicated polyposis registries that coordinate surveillance across a whole family and follow people through the transition from pediatric to adult care, which is a point at which follow-up is otherwise easily lost. Patient organizations for these conditions connect families managing the same decisions.

Questions to ask your doctor

Which gene was involved, and do I have FAP, attenuated FAP, or MUTYH-associated polyposis?
If my result involves MUTYH, was one copy affected or both?
How many polyps do I have, and how quickly are they developing?
When should I have my first colonoscopy, and how often afterward?
Will I need surgery, and if so, roughly when?
Which operation would you suggest for me, and what would bowel function be like afterward?
If my rectum is left in place, what surveillance will it need?
When should my upper endoscopy start, and what did the scoring show?
What other examinations do I need, such as thyroid or desmoid surveillance?
Which of my relatives should be tested, and at what age?
If I have MAP, should my partner be tested to find out whether our children are at risk?
Should I be followed by a specialist polyposis center or registry?
Are there medications or clinical trials that would apply to me?