Hereditary colorectal cancer syndromes

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Hereditary colorectal-cancer assessment combines tumour phenotype, germline testing and an exact family pedigree. Lynch syndrome results from a pathogenic mismatch-repair gene variant and raises colorectal and extracolonic cancer risk without producing diffuse polyposis. APC-associated familial adenomatous polyposis creates hundreds to thousands of adenomas, while biallelic MUTYH variants cause autosomal-recessive polyposis with a different pattern of risk to relatives.

Mismatch-repair immunohistochemistry or microsatellite-instability testing screens a colorectal tumour for Lynch syndrome, but an abnormal result is not automatically germline disease. Loss patterns guide BRAF V600E or MLH1 methylation testing and clinical genetics. A confirmed variant then determines colonoscopy, prophylactic surgery, extracolonic care and predictive testing. NICE also supports considering daily aspirin for more than two years in Lynch syndrome after an individual benefit, bleeding and off-label discussion.

BSG hereditary surveillance is gene and phenotype specific. MLH1 and MSH2 carriers have colonoscopy every two years from age 25 to 75; MSH6 and PMS2 carriers start the same two-year interval at 35. In classic FAP, lower-GI surveillance begins at 12–14 every one to three years according to phenotype and upper-GI surveillance begins at 25. Biallelic MUTYH-associated polyposis uses annual lower-GI surveillance from 18–20 and upper-GI surveillance from 35. After surgery, any retained rectum, pouch or other at-risk mucosa still needs its own scheduled examination.

Key points

Lynch syndrome results from pathogenic mismatch-repair variants and often presents with colorectal or endometrial cancer at younger age.
Familial adenomatous polyposis causes hundreds to thousands of adenomas through APC dysfunction and near-certain cancer risk without colectomy.
MUTYH-associated polyposis is autosomal recessive, so siblings may be at higher risk than each child.
Universal or systematic tumour mismatch-repair testing can identify cancers needing germline assessment.
Lynch colonoscopy is every two years: MLH1/MSH2 from 25 and MSH6/PMS2 from 35, continuing to 75 in BSG guidance; operations do not cancel surveillance of retained bowel.
FAP lower-GI surveillance begins at 12–14 every one to three years by phenotype and upper-GI surveillance at 25; biallelic MUTYH surveillance starts annually at 18–20 with upper-GI surveillance from 35.
NICE advises considering daily aspirin for more than two years to reduce colorectal-cancer risk in Lynch syndrome after individual discussion.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Mismatch-repair gene pathogenic variants

Heterozygous pathogenic MLH1, MSH2, MSH6, PMS2 or EPCAM-related alterations cause autosomal-dominant Lynch syndrome after a second somatic hit disables tumour mismatch repair.

APC or biallelic MUTYH dysfunction

Autosomal-dominant APC loss drives classical or attenuated FAP through Wnt activation, while recessive MUTYH loss impairs base-excision repair of oxidative DNA damage.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Microsatellite instability
Unrepaired replication errors accumulate at microsatellites and coding regions, generating a hypermutated colorectal tumour phenotype and risk across several Lynch-associated organs.
2
Constitutive Wnt activation
APC loss permits beta-catenin signalling and widespread adenoma initiation; the vast number of precursor lesions makes eventual colorectal cancer highly likely without control.
3
Oxidative base damage
Biallelic MUTYH failure allows G-to-T transversions and progressive adenoma formation, usually with fewer polyps and a recessive pedigree unlike classical FAP.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Lynch-spectrum family history

Young colorectal or endometrial cancer, multiple Lynch-associated tumours and affected relatives across generations raise suspicion, but absence of a striking pedigree does not exclude a de novo or small-family presentation.

Mismatch-repair loss pattern

Loss of MSH2, MSH6 or isolated PMS2 more directly prompts germline assessment, whereas MLH1/PMS2 loss requires reflex testing for common sporadic MLH1 silencing.

APC-associated polyposis phenotype

Hundreds to thousands of colorectal adenomas from adolescence strongly suggest FAP; desmoid, duodenal, thyroid and congenital retinal features can support the diagnosis.

Autosomal-recessive MUTYH inheritance

A person with biallelic MUTYH variants may have few affected generations; siblings have substantial carrier or disease implications, while each child is at least a carrier unless the other parent also carries a variant.

Exact pedigree data

Record maternal or paternal lineage, each tumour site, age at diagnosis, polyps and verified pathology because “bowel problems in the family” cannot select a genetic test or surveillance protocol.

Red flags requiring action

A hereditary label or scheduled colonoscopy does not protect against obstruction, perforation or major bleeding; new distension, vomiting, obstipation, peritonism or shock needs emergency colorectal assessment.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Four-protein MMR immunohistochemistry or MSI testingFirst step
Why
Screen a newly diagnosed colorectal cancer for deficient mismatch repair and possible Lynch syndrome.
Interpretation and limitations
The missing-protein pattern directs reflex tumour tests and germline genes; dMMR may be sporadic and must not be called inherited without confirmation.
02
BRAF V600E and MLH1 promoter methylation after MLH1/PMS2 loss
Why
Distinguish common sporadic MLH1 silencing from a tumour requiring germline Lynch assessment.
Interpretation and limitations
BRAF V600E or MLH1 hypermethylation supports a sporadic pathway; absent reflex findings plus clinical context prompt genetics-led germline testing.
03
Germline multigene testing
Why
Confirm a pathogenic inherited variant in MMR, APC, MUTYH or another relevant polyposis gene.
Interpretation and limitations
A pathogenic or likely pathogenic variant can direct care; a variant of uncertain significance must not be used as if disease-causing.
04
High-quality colonoscopy with polyp count and histology
Why
Define phenotype, cancer burden and residual colorectal risk before surveillance or prophylactic surgery.
Interpretation and limitations
Document number, distribution, size, dysplasia, completeness and remaining rectum or pouch; vague “multiple polyps” is inadequate.
05
Cascade predictive testing
Why
Identify relatives who carry the verified familial pathogenic variant.
Interpretation and limitations
A true-negative relative can often avoid syndrome-level surveillance, while a carrier enters the gene-specific pathway with appropriate consent.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Sporadic MLH1 hypermethylation

An older-onset tumour with MLH1/PMS2 loss may result from somatic promoter methylation; BRAF and methylation reflex testing prevent automatic mislabelling as Lynch syndrome.

Polymerase-proofreading or other polyposis syndrome

POLE, POLD1, NTHL1, hamartomatous and serrated syndromes can produce multiple lesions but differ in histology, inheritance and extracolonic risk.

Familial clustering without an identified variant

Shared environment, chance and undiscovered genetics can produce a strong family history despite negative current testing; management then follows empiric family-risk guidance.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Worked case: MLH1 and PMS2 lossDistinguish tumour screening from confirmed germline Lynch syndromeFirst stepA 42-year-old with right-sided colon cancer has loss of MLH1 and PMS2 on tumour immunohistochemistry. Their mother had endometrial cancer at 48 and maternal uncle had colon cancer at 51.

1Construct a three-generation pedigree with verified tumour sites and ages and explain that the IHC result shows deficient mismatch repair but is not itself a Lynch diagnosis.
2Arrange reflex tumour testing: BRAF V600E is absent and MLH1 promoter methylation is not detected, so the common sporadic MLH1-silencing route is less likely.
3Refer to clinical genetics for consented germline testing, including implications for relatives, reproductive choices and possible uncertain findings.
4Germline testing confirms a pathogenic MLH1 variant. Revise surgical and surveillance planning to the confirmed syndrome and discuss Lynch-associated extracolonic risk and daily aspirin for more than two years.
5Verify that the patient is enrolled in gene-specific colonoscopy follow-up and that adult relatives receive access to predictive testing for the exact familial variant.

02APC-associated FAP in adolescenceUse polyp burden and rectal phenotype to plan prophylactic surgeryA 17-year-old whose parent has FAP has a confirmed familial APC pathogenic variant and colonoscopy shows more than 500 adenomas, including dense rectal polyposis but no invasive cancer.

1Review colonoscopic distribution, dysplasia, symptoms, growth and whether adenomas remain endoscopically controllable; record thyroid examination and a future upper-GI surveillance appointment for age 25, because this asymptomatic 17-year-old has no separate indication for an earlier upper endoscopy.
2Discuss timing of prophylactic colorectal surgery before cancer develops, incorporating education, family support, fertility and the person’s capacity to adhere to long-term surveillance.
3Dense rectal disease makes rectum-preserving colectomy unsuitable, so the polyposis MDT recommends proctocolectomy with ileal pouch-anal anastomosis after shared decision-making.
4Pathology confirms adenomatous polyposis without carcinoma. Verify postoperative pouch and retained mucosal surveillance and ongoing duodenal, desmoid and thyroid risk management.

03Biallelic MUTYH resultExplain recessive inheritance and test relatives accuratelyA 48-year-old with 28 adenomas has two pathogenic MUTYH variants in trans. Their parents have no cancer history, one sibling is 45 and their partner’s carrier status is unknown.

1Confirm that the two variants are biallelic and review the colonoscopy for cancer, size, distribution, histology and whether the burden remains endoscopically manageable.
2Explain autosomal-recessive inheritance: the unaffected-looking family history is compatible, siblings need genetics assessment, and a child’s disease risk depends on the other parent’s carrier status.
3Enter the patient into the specialist MUTYH-associated polyposis pathway, using colonoscopic control or surgery according to phenotype rather than copying the FAP operation automatically.
4Verify cascade-testing offers, partner testing discussion when relevant to reproductive risk, and completion of the next colonoscopic and upper-GI surveillance appointments.

Key medicines and prescribing safety1 treatment · regimens, roles and cautions

Reduces future colorectal-cancer risk in many people with confirmed Lynch syndrome but does not replace gene-specific colonoscopy. Published CaPP3 found similar observed cancer-risk characteristics with 100 mg and fewer adverse and bleeding events, but formal non-inferiority was not established across all prespecified analyses and the active-dose comparison did not establish a placebo-relative risk reduction.

Aspirin for Lynch-syndrome colorectal-cancer prevention

NICE recommends considering aspirin daily for more than two years but does not specify an optimal dose. CAPP2 used 600 mg daily, while 150 mg or 300 mg are commonly used in UK practice; select and document an individual dose with the specialist team rather than presenting CaPP3 as a NICE dose change.

This is an off-label prevention use. Review peptic-ulcer or bleeding history, anticoagulants and antiplatelets, anaemia, hypersensitivity, asthma and renal risk, and use the NICE decision aid to discuss delayed benefit and bleeding uncertainty.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Metachronous colorectal cancer

Residual colon or rectum remains at gene-dependent risk after segmental or rectum-preserving surgery and therefore needs continuing high-quality surveillance.

Extracolonic malignancy

Lynch syndrome increases endometrial and several other cancer risks, while FAP can cause duodenal, desmoid and thyroid disease requiring syndrome-specific care.

Polyposis beyond endoscopic control

Increasing number, size or dysplasia can make reliable clearance impossible and prompt prophylactic colectomy or proctocolectomy before invasive cancer develops.

Aspirin-related bleeding

Long-term aspirin may cause dyspepsia, ulceration or gastrointestinal bleeding; benefit emerges late and must be balanced against individual haemorrhagic risk.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Track gene-specific lower-GI surveillance explicitly: MLH1/MSH2 every two years from 25, MSH6/PMS2 every two years from 35, FAP from 12–14 every one to three years, and biallelic MUTYH annually from 18–20, with interval and stopping decisions individualised to phenotype and fitness.
Record upper-GI surveillance from age 25 in FAP and 35 in MUTYH-associated polyposis, and continue examination of a retained rectum, ileal pouch or other at-risk mucosa after colorectal surgery.
Review aspirin adherence, dyspepsia, bruising, bleeding and new anaemia and revisit the dose or continued suitability without cancelling colonoscopic surveillance.
Confirm that extracolonic surveillance or symptom education matches the actual syndrome and gene rather than applying one generic hereditary-cancer list.
Maintain a record of the exact familial variant and which adult relatives have accepted, declined or not yet accessed predictive testing, respecting confidentiality.
Escalate new bleeding, anaemia, abdominal pain, obstruction symptoms or rapidly changing polyp burden outside the routine interval.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Pedigrees need exact ages

Age and lineage distinguish sporadic clustering from patterns that meet genetics referral criteria.

Tumour and germline tests differ

A tumour phenotype guides probability; inherited status requires germline confirmation and expert interpretation.

Surgery is phenotype-specific

Polyp burden, cancer, rectal involvement and patient goals determine colectomy extent.

Relatives gain prevention

Cascade testing concentrates surveillance on carriers and releases non-carriers from unnecessary high-intensity pathways.

11Common pitfallsFrequent interpretation and management errors.

01
Calling all MLH1 loss Lynch syndrome ignores common sporadic methylation and reflex-testing steps.
02
Testing children for adult-onset risk without genetics guidance can violate consent and timing principles.
03
Treating a variant of uncertain significance as pathogenic can trigger harmful surveillance or surgery.
04
Stopping follow-up after colectomy overlooks residual rectum, pouch or extracolonic syndrome risks.

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