Hereditary bowel cancer syndromes (Lynch syndrome and FAP)
Most bowel cancer is not inherited. Around one case in twenty, however, is caused by a fault in a single gene passed down through a family, and identifying those families matters more than almost anything else in colorectal practice. The reason is simple: in an ordinary case of bowel cancer, the diagnosis concerns one person. In an inherited syndrome, the diagnosis concerns everyone who shares that gene — and for them, surveillance and preventive treatment can stop a cancer ever occurring.
Lynch syndrome
How it arises
Lynch syndrome, formerly called hereditary non-polyposis colorectal cancer, is the commonest inherited cause of bowel cancer. It is caused by an inherited fault in one of the mismatch repair genes — MLH1, MSH2, MSH6 or PMS2 — or in EPCAM, which silences MSH2.
The mismatch repair system is a proofreading mechanism. Each time a cell divides, it copies three billion base pairs of DNA, and the copying machinery makes errors — particularly in repetitive stretches of sequence called microsatellites, where it is prone to slipping. Mismatch repair proteins detect and correct those errors.
A person with Lynch syndrome inherits one faulty copy of the gene in every cell. That alone causes no harm, because the second copy works. But over a lifetime, in one cell somewhere in the colon, the second copy is lost by chance — the "second hit". That cell now has no proofreading. Errors accumulate at up to a thousand times the normal rate, particularly in microsatellites, producing microsatellite instability. Genes controlling growth are hit quickly, and cancer follows.
Two practical consequences follow from this mechanism:
- Progression is fast. An adenoma in Lynch syndrome may become a cancer in two to three years rather than ten to fifteen. This is why surveillance colonoscopy is performed every one to two years, not every five or ten, and why interval cancers still occur.
- The tumours are highly immunogenic. The huge mutation load produces abnormal proteins the immune system recognises as foreign. This is why Lynch-associated cancers respond exceptionally well to immunotherapy — a genuinely major advance for these patients.
What it causes
Lifetime risks vary considerably by which gene is affected — MLH1 and MSH2 carry substantially higher risks than MSH6 and PMS2, and surveillance is now tailored accordingly.
- Colorectal cancer — the principal risk, typically at a younger age than sporadic cancer, more often in the right colon, and with a significant risk of a second primary cancer in the remaining bowel
- Endometrial cancer — in women, a risk comparable to or exceeding that of bowel cancer, and frequently the first cancer to occur
- Ovarian, gastric, small bowel, pancreatic, urinary tract, biliary and brain tumours, and sebaceous skin tumours (Muir-Torre variant)
How it is identified
- Universal testing of all colorectal and endometrial cancers for mismatch repair deficiency, by immunohistochemistry for the four proteins or by microsatellite instability testing. This is now standard practice, and it is the single most effective way of identifying Lynch families — far more effective than relying on family history, which is often incomplete or unknown.
- Where MLH1 is lost, BRAF mutation testing and MLH1 promoter methylation testing distinguish sporadic mismatch repair deficiency (common, acquired, not inherited) from true Lynch syndrome.
- Germline genetic testing on a blood or saliva sample confirms the diagnosis, and allows predictive testing of relatives.
- Clinical criteria — the Amsterdam criteria and revised Bethesda guidelines — remain useful prompts but miss many cases and have largely been superseded by universal tumour testing.
Management
- Colonoscopy every one to two years, beginning in the twenties or thirties depending on the gene. Quality matters enormously, given how fast lesions progress.
- Aspirin — the CAPP2 trial showed that regular aspirin substantially reduces colorectal cancer incidence in Lynch syndrome, with the benefit emerging after several years. Dose and duration are individualised.
- Surgery for cancer — because the remaining colon carries a significant risk of a further primary cancer, extended resection (subtotal colectomy) rather than segmental resection is often recommended, particularly in younger patients. This is a real trade-off — more frequent, looser bowel motions against a lower risk of a second cancer — and the patient should be part of that decision.
- Risk-reducing hysterectomy and bilateral salpingo-oophorectomy for women, usually considered after childbearing is complete. Endometrial surveillance is of less proven value.
- Upper gastrointestinal endoscopy and consideration of H. pylori eradication; urinary and other surveillance according to gene and family history.
- Immunotherapy for advanced disease, where response rates are high and durable.
- Cascade testing of relatives — the most valuable single action, since each first-degree relative has a one-in-two chance of carrying the gene.
Familial adenomatous polyposis (FAP)
How it arises
FAP is caused by an inherited fault in the APC gene, the gatekeeper of the Wnt signalling pathway that controls renewal of the bowel lining. With one copy already faulty in every cell, loss of the second copy occurs in thousands of cells across the colon over the years of childhood and adolescence. The result is hundreds to thousands of adenomatous polyps carpeting the colon and rectum, usually appearing in the teenage years.
Each polyp behaves like an ordinary adenoma. With thousands of them, cancer becomes a near-certainty — the lifetime risk approaches one hundred per cent if the colon is left in place, with cancer typically occurring in the thirties or forties. Around a quarter of cases arise from a new mutation with no family history at all.
Attenuated FAP is a milder variant, with fewer polyps (typically under a hundred), more right-sided distribution, later onset and later cancer.
MUTYH-associated polyposis is a separate condition caused by faults in both copies of the MUTYH gene, inherited recessively — so it may appear in siblings without affecting parents or children. It produces a polyp burden between attenuated FAP and ordinary practice.
What else it causes
FAP is not confined to the colon, and after colectomy these become the leading causes of illness:
- Duodenal and ampullary adenomas — near-universal, and duodenal cancer is a leading cause of death after colectomy. Surveillance uses a side-viewing endoscope and the Spigelman staging system.
- Desmoid tumours — locally aggressive fibrous tumours, often intra-abdominal in the mesentery, frequently triggered by surgery. They do not metastasise but can be extremely difficult to manage.
- Gastric fundic gland polyps; thyroid cancer, particularly in women; hepatoblastoma in young children; osteomas; epidermoid cysts; and congenital hypertrophy of the retinal pigment epithelium, a harmless retinal finding useful as a marker.
Management
- Genetic testing and predictive testing of at-risk children, usually offered around ten to twelve years of age, timed to when surveillance would begin.
- Annual sigmoidoscopy or colonoscopy from early adolescence.
- Prophylactic colectomy — the central intervention, timed according to polyp burden, usually in the late teens or early twenties, and planned around education and life circumstances where the polyp burden allows. The options:
- Total colectomy with ileorectal anastomosis — simpler, better function, preserves fertility better, but leaves the rectum requiring lifelong six-monthly to annual surveillance and carrying a continuing cancer risk. Suitable where rectal polyps are few.
- Proctocolectomy with ileal pouch-anal anastomosis — removes almost all at-risk mucosa, at the cost of more frequent bowel motions and, in women, reduced fertility. Preferred where the rectum is heavily affected.
The choice depends on the polyp burden in the rectum, the specific APC mutation, and the patient's own priorities, and it is an important conversation, not a technical default.
- Lifelong upper gastrointestinal surveillance, with endoscopic or surgical treatment of advanced duodenal disease.
- Thyroid ultrasound surveillance, and management of desmoid disease in a specialist centre.
Other syndromes
- Peutz-Jeghers syndrome (STK11) — hamartomatous polyps, characteristic pigmented spots on the lips and buccal mucosa, small bowel intussusception, and a raised risk of several cancers.
- Juvenile polyposis syndrome (SMAD4, BMPR1A) — multiple juvenile polyps; SMAD4 cases overlap with hereditary haemorrhagic telangiectasia.
- PTEN hamartoma tumour syndrome (Cowden syndrome) — polyps with breast, thyroid and endometrial cancer risk.
- Serrated polyposis syndrome — multiple and large serrated lesions, with increased colorectal cancer risk; the genetic basis is largely unknown, but surveillance is warranted for the patient and their first-degree relatives.
When to seek an opinion
Genetic assessment should be considered where there is: bowel cancer under the age of fifty; more than one relative with bowel or related cancer; a personal history of more than one Lynch-associated cancer; endometrial cancer under fifty; more than ten cumulative bowel polyps; a tumour reported as mismatch repair deficient; or a known family mutation. If in doubt, ask — the cost of a referral is small and the cost of missing a syndrome is borne by a whole family.
Common questions
My father had bowel cancer. Does that mean I have an inherited syndrome?
Usually not. Most bowel cancer is not inherited, and having one affected relative raises your risk modestly without indicating a single-gene condition. What raises the suspicion is cancer at a young age, several affected relatives, more than one cancer in the same person, or a large number of polyps.
What does it mean if my tumour was tested and found to be "mismatch repair deficient"?
It means the proofreading system in the tumour was not working. In most cases this is an acquired change in the tumour only and is not inherited, and a further test distinguishes the two. Where it is inherited, it indicates Lynch syndrome, which matters for your relatives and for your own future surveillance. It also has an immediate benefit: these tumours respond particularly well to immunotherapy.
Why do I need a colonoscopy every one or two years rather than every five?
Because in Lynch syndrome the proofreading failure means a polyp can become a cancer in two or three years rather than over a decade. The interval is set by how fast the process runs, not by how many polyps are found.
Should my children be tested?
For Lynch syndrome, testing is usually offered in adulthood, ahead of when surveillance would begin. For familial adenomatous polyposis, testing is offered in early adolescence, because polyps and the need for surveillance begin then. Genetic counselling is part of this and covers the implications before any test is done.
If I have the gene, will I definitely get cancer?
No. In Lynch syndrome the risk is substantial but far from certain, and it varies considerably depending on which gene is affected. With regular colonoscopy, and aspirin, the risk falls significantly. In familial adenomatous polyposis with a full polyp burden, cancer is close to certain if the colon is left in place — which is precisely why preventive surgery is recommended, and why it works.
Why remove the whole colon rather than just the affected part?
Because in these conditions the whole lining carries the fault, so the remaining bowel continues to form polyps and can develop a second cancer. In familial polyposis this is near-certain; in Lynch syndrome it is a significant risk, and an extended operation is often recommended, particularly in younger patients. It is a genuine trade-off against bowel function, and you should be part of that decision.
Does aspirin really help?
In Lynch syndrome, yes — a long-term trial showed a substantial reduction in bowel cancer in people taking regular aspirin, with the benefit appearing after several years. The right dose and duration are decided individually, taking into account the risk of stomach irritation and bleeding.
I have no family history at all. Can I still have one of these conditions?
Yes. About a quarter of cases of familial adenomatous polyposis arise from a brand-new genetic change with no family history. One polyposis condition is inherited in a way that can affect siblings while skipping parents and children entirely. And family histories are often incomplete — which is exactly why all bowel cancers are now tested directly rather than relying on the family tree.
Related conditions
Other conditions of the colon & rectum covered on this site:
- Colon cancer
- Rectal cancer
- Bowel polyps (colorectal polyps)
- Diverticular disease and diverticulitis
- Crohn's disease — the surgical perspective
- Ulcerative colitis — the surgical perspective
- Large bowel obstruction and volvulus
- Appendicitis
This page provides general information and does not replace an individual medical consultation. Genetic testing is undertaken with formal genetic counselling, and management is individualised for each patient and family.